Solid Forms Of an HIV Capsid Inhibitor

ABSTRACT

The present disclosure relates to pharmaceutically acceptable salts, cocrystals, and crystalline forms thereof, of a compound which is N—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1 -yl)pyridin-2-yl)-2-(3,5-difluorophenypethyl)-2- ((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, which is useful in the treatment of a Retroviridae viral infection including an infection caused by the HIV virus.

TECHNICAL FIELD

The present disclosure relates to solid forms of an HIV capsidinhibitor, including pharmaceutically acceptable salts and cocrystals ofthe inhibitor, as well as crystalline forms of the salts and cocrystals,for use in the treatment of a Retroviridae viral infection including aninfection caused by the HIV virus. The present disclosure also relatesto pharmaceutical compositions containing the novel salts, cocrystals,and crystalline forms thereof, and methods of treating or preventing aRetroviridae viral infection.

BACKGROUND

Positive-single stranded RNA viruses comprising the Retroviridae familyinclude those of the subfamily Orthoretrovirinae and generaAlpharetrovirus, Betaretrovirus, Gammaretrovirus, Deltaretrovirus,Epsilonretrovirus, Lentivirus, and Spumavirus which cause many human andanimal diseases. Among the Lentivirus, HIV-1 infection in humans leadsto depletion of T helper cells and immune dysfunction, producingimmunodeficiency and vulnerability to opportunistic infections. TreatingHIV-1 infections with highly active antiretroviral therapies (HAART) hasproven to be effective at reducing viral load and significantly delayingdisease progression (Hammer, S. M., et al.; JAMA 2008, 300: 555-570).However, these treatments could lead to the emergence of HIV strainsthat are resistant to current therapies (Taiwo, B., InternationalJournal of Infectious Diseases 2009, 13:552-559; Smith, R. J., et al.,Science 2010, 327:697-701). Therefore, there is an ongoing need todiscover new antiretroviral agents and to develop methods for theirpreparation and purification as well as prepare improved pharmaceuticalformulations of the same. The solid forms of the HIV capsid inhibitordisclosed herein help meet these and other needs.

SUMMARY

The present application provides a solid form of Compound 1:

which includes a salt or cocrystal of Compound 1, as well as acrystalline form of the salt or cocrystal.

The present application further provides a pharmaceutical compositioncomprising the pharmaceutically acceptable salt, cocrystal, orcrystalline form of Compound 1 disclosed herein, and at least onepharmaceutically acceptable excipient.

The present application further provides a crystalline form of thepharmaceutically acceptable salt or cocrystal of Compound 1.

The present application further provides methods of treating orpreventing a human immunodeficiency virus (HIV) infection comprisingadministering a therapeutically effective amount of a pharmaceuticallyacceptable salt, cocrystal, or crystalline form of the invention to asubject in need thereof.

The present application further provides the pharmaceutically acceptablesalt, cocrystal, and crystalline form of the present invention for usein therapy.

The present application further provides the pharmaceutically acceptablesalt, cocrystal, or crystalline form of the present invention for use ina method of treating or preventing a human immunodeficiency virus (HIV)infection, comprising administering a therapeutically effective amountof the salt, cocrystal, or crystalline form to a subject in needthereof.

The present application further provides a process of increasing theamount of an isomeric compound of Isomer A:

relative to an amount of an isomeric compound of Isomer B:

or the amount of an isomeric compound of Isomer B relative to the amountof an isomeric compound of Isomer A, in a starting mixture comprisingboth isomeric compounds, the process comprising:

contacting the starting mixture with an acid or a base in the presenceof a solvent to form a salt mixture of both isomeric compounds, whereinthe salt mixture has an increased amount of the isomeric salt of IsomerA relative to the amount of the isomeric salt of Isomer B, or anincreased amount of the isomeric salt of Isomer B relative to the amountof the isomeric salt of Isomer A, when compared with the relativeamounts of the isomeric compounds of Isomer A and Isomer B in thestarting mixture.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an XRPD pattern characteristic of the sodium salt ofCompound 1, crystalline Form I.

FIG. 2 shows a DSC thermogram characteristic of the sodium salt ofCompound 1, crystalline Form I.

FIG. 3 shows an XRPD pattern characteristic of the sodium salt ofCompound 1, crystalline Form II.

FIG. 4 shows a DSC thermogram characteristic of the sodium salt ofCompound 1, crystalline Form II.

FIG. 5 shows an XRPD pattern characteristic of the sodium salt ofCompound 1, crystalline Form III.

FIG. 6 shows a DSC thermogram characteristic of the sodium salt ofCompound 1, crystalline Form III.

FIG. 7 shows an XRPD pattern characteristic of the potassium salt ofCompound 1.

FIG. 8 shows an XRPD pattern characteristic of the methanesulfonic acidsalt or cocrystal of Compound 1, crystalline Form I.

FIG. 9 shows a DSC thermogram characteristic of the methanesulfonic acidsalt or cocrystal of Compound 1, crystalline Form I.

FIG. 10 shows an XRPD pattern characteristic of the methanesulfonic acidsalt or cocrystal of Compound 1, crystalline Form II.

FIG. 11 shows a DSC thermogram characteristic of the methanesulfonicacid salt or cocrystal of Compound 1, crystalline Form II.

FIG. 12 shows a single crystal X-ray diffraction (SCXRD) molecularrepresentation of the dichloromethane solvate form of themethanesulfonic acid salt of Compound 1.

FIG. 13 shows an XRPD pattern characteristic of the methanesulfonic acidsalt or cocrystal of Compound 1, crystalline Form III.

FIG. 14 shows a DSC thermogram characteristic of the methanesulfonicacid salt or cocrystal of Compound 1, crystalline Form III.

FIG. 15 shows an XRPD pattern characteristic of the methanesulfonic acidsalt or cocrystal of Compound 1, crystalline Form IV (hydrate).

FIG. 16 shows an XRPD pattern characteristic of the ethanesulfonic acidsalt or cocrystal of Compound 1.

FIG. 17 shows a DSC thermogram characteristic of the ethanesulfonic acidsalt or cocrystal of Compound 1.

FIG. 18 shows an XRPD pattern characteristic of the benzenesulfonic acidsalt or cocrystal of Compound 1.

FIG. 19 shows a DSC thermogram characteristic of the benzenesulfonicacid salt or cocrystal of Compound 1.

FIG. 20 shows an XRPD pattern characteristic of the hydrochloric acidsalt or cocrystal of Compound 1, crystalline Form I.

FIG. 21 shows a DSC thermogram characteristic of the hydrochloric acidsalt or cocrystal of Compound 1, crystalline Form I.

FIG. 22 shows an XRPD pattern characteristic of the hydrochloric acidsalt or cocrystal of Compound 1, crystalline Form II.

FIG. 23 shows an XRPD pattern characteristic of the hydrochloric acidsalt or cocrystal of Compound 1, crystalline Form III.

FIG. 24 shows a DSC thermogram characteristic of the hydrochloric acidsalt or cocrystal of Compound 1, crystalline Form III.

FIG. 25 shows an XRPD pattern characteristic of the sulfuric acid saltor cocrystal of Compound 1.

FIG. 26 shows a DSC thermogram characteristic of the sulfuric acid saltor cocrystal of Compound 1.

FIG. 27 shows a plot of plasma concentration over time of 200 mg/mL ofCompound 1, sodium salt in 2% poloxamer 188 in saline whensubcutaneously dosed in dogs at 6 mg/kg.

FIG. 28 shows a plot of plasma concentration over time of 200 mg/mL ofCompound 1, sodium salt form dissolved in NMP, after subcutaneous dosingin dogs at 6 mg/kg.

FIG. 29 shows a plot of plasma concentration over time of 200 mg/mL ofCompound 1, in situ sodium salt, in 10% ethanol, 13% water, and 77% PEG200 when dosed subcutaneously in subjects at 6 mg/kg.

FIG. 30 shows a plot of plasma concentration over time of 200 mg/mL ofCompound 1 in 10% ethanol, 13% water, and 77% glycofurol, with 1.2mol-eq. NaOH to form in situ Na salt when dosed in subjects at 6 mg/kg.

DETAILED DESCRIPTION

The present invention relates to new solid forms of the HIV capsidinhibitorN—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(i.e., Compound 1, see below). One skilled in the art understands that acompound structure may be named or identified using commonly recognizednomenclature systems and symbols. By way of example, the compound may benamed or identified with common names, systematic or non-systematicnames. The nomenclature systems and symbols that are commonly recognizedin the art of chemistry including but not limited to Chemical AbstractService (CAS) and International Union of Pure and Applied Chemistry(IUPAC). Accordingly, the compound structure for Compound 1 providedabove may also be named or identified asN—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide.

Compound 1 can be a weak acid (pKa 6.7 at sulfonamide) or a weak base(pKa <1 at pyridine) and consists of two atropisomers, Isomer A andIsomer B, that can rotate along one of the C—C bonds, as shown below. Insolution, the two atropisomers coexist in the ratio of about 1:5 to 1:8(Isomer A:Isomer B), depending on temperatures and pH.

The two atropisomers can be separated by chromatography but theyre-equilibrate in solution (t1/2 1-2 hours at 37° C.) and the rotationalenergy barrier is about 24 kcal/mol.

As described herein, Isomer B can be enriched by crystallization. Forexample, Isomer B can be enriched by preparing Form I of the sodium saltand Forms I/III of the methanesulfonic acid salt (or cocrystal).

The solid forms of the invention include salt forms (both amorphous andcrystalline) as well as cocrystal forms of Compound 1. As used herein,“solid form” generally refers to a solid chemical substance that can beamorphous or crystalline. In some embodiments, the solid form of theinvention is a salt of Compound 1 which can be amorphous or crystalline.In further embodiments, the solid form can be a cocrystal of Compound 1,in which Compound 1 has formed a crystalline solid together with acoformer molecule. Both crystalline salts and cocrystals of Compound 1can exist in different crystalline forms (i.e., have differentpolymorphic or pseudopolymorphic forms).

As used herein, the term “cocrystal” refers to a compound (such asCompound 1) crystallized together with one or more coformer molecules(e.g., molecules other than the compound). Depending on the chemicalnature and proportion of coformers present in the cocrystal, differentphysical properties related to, for example, dissolution and solubilitymay be observed compared with solid forms of the compound by itself orsalts thereof. In some instances, the coformer molecule may be a proticacid, and whether the protic acid forms a salt or a cocrystal will oftendepend on the relative pKa's of the compound and coformer. See, e.g.,Regulatory Classification of Pharmaceutical Co-Crystals: Guidance forIndustry, revised August 2016, published by the U.S. Dept. of Health andHuman Services, FDA, Center for Drug Evaluation and Research (CDER).

As used herein, “crystalline form” is meant to refer to a certainlattice configuration of a crystalline substance (e.g., a salt or acocrystal). Different crystalline forms of the same substance typicallyhave different crystalline lattices (e.g., unit cells) which areattributed to different physical properties that are characteristic ofeach of the crystalline forms. In some instances, different latticeconfigurations have different water or solvent content.

According to the present invention, a crystalline form of a salt orcocrystal of Compound 1 can be useful in the synthesis and/orpurification of Compound 1. For example, a crystalline form of a salt orcocrystal of Compound 1 can be an intermediate in the synthesis ofCompound 1. In addition, different crystalline forms of salts andcocrystals of Compound 1 may have different properties with respect tobioavailability, stability, purity, and/or manufacturability for medicalor pharmaceutical uses. Variations in the crystal structure of apharmaceutical drug substance or active ingredient may affect thedissolution rate (which may affect bioavailability, etc.),manufacturability (e.g., ease of handling, ability to consistentlyprepare doses of known strength), and stability (e.g., thermalstability, shelf life, etc.) of a pharmaceutical drug product or activeingredient. Such variations may affect the preparation or formulation ofpharmaceutical compositions in different dosage or delivery forms, suchas solutions or solid oral dosage form including tablets and capsules.Compared to other forms such as non-crystalline or amorphous forms,crystalline forms may provide desired or suitable hygroscopicity,particle size controls, dissolution rate, solubility, purity, physicaland chemical stability, manufacturability, yield, and/or processcontrol. Thus, the crystalline forms of the salts and cocrystals ofCompound 1 may provide advantages such as improving the manufacturingprocess of the compound, the stability or storability of a drug productform of the compound, the stability or storability of a drug substanceof the compound and/or the bioavailability and/or stability of thecompound as an active agent.

The use of certain solvents and/or processes have been found to producedifferent crystalline forms of the salts and cocrystals of Compound 1which may exhibit one or more of the favorable characteristics describedabove. The processes for the preparation of the crystalline andcocrystal forms described herein and characterization of thesecrystalline and cocrystal forms are described in detail below.

In some embodiments, the pharmaceutically acceptable salts describedherein, cocrystals, or crystalline forms thereof, are purified orsubstantially isolated. By “substantially isolated” is meant that thesalt, cocrystal, or crystalline form thereof is at least partially orsubstantially separated from the environment in which it was formed ordetected. Partial separation can include, for example, a compositionenriched in the salt, cocrystal, or crystalline form of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the salt, cocrystal, or crystalline form of theinvention. In some embodiments, the salt, cocrystal, or crystalline formof the invention can be prepared with a purity of about 75% or more, 80%or more, 85% or more, 90% or more, 95% or more, 98% or more, or 99% ormore.

The different crystalline forms can be identified by solid statecharacterization methods such as by X-ray powder diffraction (XRPD).Other characterization methods such as differential scanning calorimetry(DSC) further help identify the form as well as help determine stabilityand solvent/water content.

An XRPD pattern of reflections (peaks) is typically considered afingerprint of a particular crystalline form. It is well known that therelative intensities of the XRPD peaks can widely vary depending on,inter alia, the sample preparation technique, crystal size distribution,various filters used, the sample mounting procedure, and the particularinstrument employed. In some instances, new peaks may be observed orexisting peaks may disappear, depending on the type of the instrument orthe settings. As used herein, the term “peak” refers to a reflectionhaving a relative height/intensity of at least about 5% of the maximumpeak height/intensity. Moreover, instrument variation and other factorscan affect the 2-theta values. Thus, peak assignments, such as thosereported herein, can vary by plus or minus about 0.2° (2-theta), and theterm “substantially” and “about” as used in the context of XRPD hereinis meant to encompass the above-mentioned variations.

In the same way, temperature readings in connection with DSC can varyabout ±3° C. depending on the instrument, particular settings, samplepreparation, etc. Accordingly, a crystalline form reported herein havinga DSC thermogram “substantially” as shown in any of the Figures or theterm “about” is understood to accommodate such variation.

The present invention provides crystalline forms of certain compounds orsalts thereof. In some embodiments, the crystalline form may besubstantially anhydrous. In some embodiments, the crystalline form maybe hydrated or solvated.

Compound 1 Sodium Salt

In some embodiments, Compound 1 can be isolated as a sodium salt whichcan be amorphous or crystalline. In some embodiments, the sodium salt ofCompound 1 is crystalline.

In some embodiments, the crystalline sodium salt of Compound 1 isselected from crystalline Form I, crystalline Form II, and crystallineForm III.

In some embodiments, crystalline Form I of the sodium salt of Compound 1has an XRPD profile substantially as shown in FIG. 1.

In some embodiments, crystalline Form I of the sodium salt of Compound 1has at least one, at least two, at least three, at least four, at leastfive, at least six, at least seven, at least eight, or at least nineXRPD peaks, in terms of 2-theta±0.2°, selected from 5.6°, 6.6°, 10.9°,13.4°, 16.8°, 17.1°, 21.8°, 24.1°, and 26.9°.

In some embodiments, crystalline Form I of the sodium salt of Compound 1is characterized by a DSC thermogram substantially as shown in FIG. 2.

In some embodiments, crystalline Form I of the sodium salt of Compound 1is characterized by a DSC thermogram having a melting onset of about218° C.

In some embodiments, crystalline Form II of the sodium salt of Compound1 has an XRPD profile substantially as shown in FIG. 3.

In some embodiments, crystalline Form II of the sodium salt of Compound1 has at least one, at least two, at least three, at least four, atleast five, at least six, at least seven, at least eight, or at leastnine XRPD peaks, in terms of 2-theta±0.2°, selected from 5.4°, 7.0°,11.1°, 17.7°, 19.2°, 21.2°, 22.6°, 24.0°, and 27.7°.

In some embodiments, crystalline Form II of the sodium salt of Compound1 is characterized by a DSC thermogram substantially as shown in FIG. 4.

In some embodiments, crystalline Form II of the sodium salt of Compound1 is characterized by a DSC thermogram having a melting onset of about222° C.

In some embodiments, crystalline Form III of the sodium salt of Compound1 has an XRPD profile substantially as shown in FIG. 5.

In some embodiments, crystalline Form III of the sodium salt of Compound1 has at least one, at least two, at least three, at least four, atleast five, at least six, at least seven, at least eight, or at leastnine XRPD peaks, in terms of 2-theta±0.2°, selected from 5.9°, 7.1°,11.6°, 15.4°, 17.2°, 18.4°, 19.5°, 22.2°, and 27.2°.

In some embodiments, crystalline Form III of the sodium salt of Compound1 is characterized by a DSC thermogram substantially as shown in FIG. 6.

In some embodiments, crystalline Form III of the sodium salt of Compound1 is characterized by a DSC thermogram having a melting onset of about213° C.

Compound 1 Potassium Salt

In some embodiments, Compound 1 can be isolated as a potassium saltwhich can be amorphous or crystalline. In some embodiments, thepotassium salt of Compound 1 is crystalline.

In some embodiments, the crystalline potassium salt of Compound 1 has anXRPD profile substantially as shown in FIG. 7.

Compound 1 Methanesulfonic Acid (Mesylate) Salt or Cocrystal

In some embodiments, Compound 1 can be isolated as a methanesulfonicacid (mesylate) salt or cocrystal which can be crystalline. In someembodiments, the methanesulfonic acid salt or cocrystal is amono-methanesulfonic acid salt or cocrystal.

In some embodiments, the crystalline methanesulfonic acid salt orcocrystal of Compound 1 is selected from crystalline Form I, crystallineForm II, crystalline Form III, and crystalline Form IV.

In some embodiments, crystalline Form I of the methanesulfonic acid saltor cocrystal of Compound 1 has an XRPD profile substantially as shown inFIG. 8.

In some embodiments, crystalline Form I of the methanesulfonic acid saltor cocrystal of Compound 1 has at least one, at least two, at leastthree, at least four, at least five, at least six, at least seven, atleast eight, or at least nine XRPD peaks, in terms of 2-theta ±0.2°,selected from 12.9°, 15.4°, 18.4°, 18.8°, 19.7°, 20.2°, 20.9°, 23.5°,and 25.3°.

In some embodiments, crystalline Form I of the methanesulfonic acid saltor cocrystal of Compound 1 is characterized by a DSC thermogramsubstantially as shown in FIG. 9.

In some embodiments, crystalline Form I of the methanesulfonic acid saltor cocrystal of Compound 1 is characterized by a DSC thermogram having amelting onset of about 130° C.

In some embodiments, crystalline Form II of the methanesulfonic acidsalt or cocrystal of Compound 1 has an XRPD profile substantially asshown in FIG. 10.

In some embodiments, crystalline Form II of the methanesulfonic acidsalt or cocrystal of Compound 1 has at least one, at least two, at leastthree, at least four, at least five, at least six, at least seven, atleast eight, or at last nine XRPD peaks, in terms of 2-theta'0.2°,selected 8.7°, 13.0°, 17.5°, 9.3°, 20.6°, 21.3°, 21.7°, 24.2°, and25.3°.

In some embodiments, crystalline Form II of the methanesulfonic acidsalt or cocrystal of Compound 1 is characterized by a DSC thermogramsubstantially as shown in FIG. 11.

In some embodiments, crystalline Form II of the methanesulfonic acidsalt or cocrystal of Compound 1 is characterized by a DSC thermogramhaving a melting onset of about 165° C.

In some embodiments, crystalline Form III of the methanesulfonic acidsalt or cocrystal of Compound 1 has an XRPD profile substantially asshown in FIG. 13.

In some embodiments, crystalline Form III of the methanesulfonic acidsalt or cocrystal of Compound 1 has at least one, at least two, at leastthree, at least four, at least five, at least six, at least seven, atleast eight, or at least nine XRPD peaks, in terms of 2-theta ±0.2°,selected from 8.2°, 11.3°, 12.8°, 15.7°, 16.9°, 20.1°, 21.8°, 22.6°, and24.7°.

In some embodiments, crystalline Form III of the methanesulfonic acidsalt or cocrystal of Compound 1 is characterized by a DSC thermogramsubstantially as shown in FIG. 14.

In some embodiments, crystalline Form III of the methanesulfonic acidsalt or cocrystal of Compound 1 is characterized by a DSC thermogramhaving a melting onset of about 141° C.

In some embodiments, the methanesulfonic acid salt or cocrystal ofCompound 1 is solvated.

In some embodiments, the methanesulfonic acid salt or cocrystal ofCompound 1 is a dichloromethane solvate. In some embodiments, themethanesulfonic acid salt or cocrystal is a bis-dichloromethane solvate.

In some embodiments, crystalline Form IV of the methanesulfonic acidsalt or cocrystal of Compound 1 is a hydrate.

In some embodiments, crystalline Form IV of the methanesulfonic acidsalt or cocrystal hydrate of Compound 1 has an XRPD profilesubstantially as shown in FIG. 15.

In some embodiments, crystalline Form IV of the methanesulfonic acidsalt or cocrystal hydrate of Compound 1 has at least one, at least two,at least three, at least four, at least five, at least six, at leastseven, at least eight, or at least nine XRPD peaks, in terms of2-theta±0.2°, selected from 7.9°, 11.1°, 12.1°, 12.7°, 16.9°, 21.2°,21.7°, 25.4°, and 26.6°.

Compound 1 Ethanesulfonic Acid (Esylate) Salt or Cocrystal

In some embodiments, Compound 1 can be isolated as an ethanesulfonicacid (esylate) salt or cocrystal which can be crystalline.

In some embodiments, the crystalline ethanesulfonic acid salt orcocrystal of Compound 1 has an XRPD profile substantially as shown inFIG. 16.

In some embodiments, the crystalline ethanesulfonic acid salt orcocrystal of Compound 1 has at least one, at least two, at least three,at least four, at least five, at least six, at least seven, at leasteight, or at least nine XRPD peaks, in terms of 2-theta±0.2°, selectedfrom 9.1°, 12.7°, 13.3°, 15.2°, 18.8°, 19.5°, 20.5°, 22.4°, and 25.3°.

In some embodiments, the crystalline ethanesulfonic acid salt orcocrystal of Compound 1 is characterized by a DSC thermogramsubstantially as shown in FIG. 17.

In some embodiments, the crystalline ethanesulfonic acid salt orcocrystal of Compound 1 is characterized by a DSC thermogram having amelting onset of about 119° C.

Compound 1 Benzenesulfonic Acid (Besylate) Salt or Cocrystal

In some embodiments, Compound 1 can be isolated as a benzenesulfonicacid (besylate) salt or cocrystal which can be crystalline.

In some embodiments, the crystalline benzenesulfonic acid salt orcocrystal of Compound 1 has an XRPD profile substantially as shown inFIG. 18.

In some embodiments, the crystalline benzenesulfonic acid salt orcocrystal of Compound 1 has at least one, at least two, at least three,at least four, at least five, at least six, at least seven, at leasteight, or at least nine XRPD peaks, in terms of 2-theta±0.2°, selectedfrom 7.5°, 8.5°, 13.6°, 17.0°, 18.5°, 18.9°, 20.0°, 21.7°, and 26.6°.

In some embodiments, the crystalline benzenesulfonic acid salt orcocrystal of Compound 1 is characterized by a DSC thermogramsubstantially as shown in FIG. 19.

Compound 1 Hydrochloric Acid Salt or Cocrystal

In some embodiments, Compound 1 can be isolated as a hydrochloric acidsalt or cocrystal which can be crystalline.

In some embodiments, the crystalline hydrochloric acid salt or cocrystalof Compound 1 is selected from crystalline Form I, crystalline Form II,and crystalline Form III.

In some embodiments, crystalline Form I of the hydrochloric acid salt orcocrystal of Compound 1 has an XRPD profile substantially as shown inFIG. 20.

In some embodiments, crystalline Form I of the hydrochloric acid salt orcocrystal of Compound 1 has at least one, at least two, at least three,at least four, at least five, at least six, at least seven, at leasteight, or at least nine XRPD peaks, in terms of 2-theta ±0.2°, selectedfrom 9.4°, 12.6°, 14.3°, 15.4°, 16.4°, 20.1°, 21.6°, 22.5°, and 23.8°.

In some embodiments, crystalline Form I of the hydrochloric acid salt orcocrystal of Compound 1 is characterized by a DSC thermogramsubstantially as shown in FIG. 21.

In some embodiments, crystalline Form I of the hydrochloric acid salt orcocrystal of Compound 1 is characterized by a DSC thermogram having amelting onset of about 101° C.

In some embodiments, crystalline Form II of the hydrochloric acid saltor cocrystal of Compound 1 has an XRPD profile substantially as shown inFIG. 22.

In some embodiments, crystalline Form II of the hydrochloric acid saltor cocrystal of Compound 1 has at least one, at least two, at leastthree, at least four, at least five, at least six, at least seven, atleast eight, or at least nine XRPD peaks, in terms of 2-theta ±0.2°,selected from 17.2°, 17.6°, 18.1°, 18.8°, 22.3°, 22.6°, 23.1°, 25.5°,and 26.9°.

In some embodiments, crystalline Form III of the hydrochloric acid saltor cocrystal of Compound 1 has an XRPD profile substantially as shown inFIG. 23.

In some embodiments, crystalline Form III of the hydrochloric acid saltor cocrystal of Compound 1 has at least one, at least two, at leastthree, at least four, at least five, at least six, at least seven, atleast eight, or at least nine XRPD peaks, in terms of 2-theta ±0.2°,selected from 9.7°, 12.9°, 16.7°, 17.6°, 18.0°, 18.5°, 19.3°, 22.1°, and25.0°.

In some embodiments, crystalline Form III of the hydrochloric acid saltor cocrystal of Compound 1 is characterized by a DSC thermogramsubstantially as shown in FIG. 24.

In some embodiments, crystalline Form III of the hydrochloric acid saltor cocrystal of Compound 1 is characterized by a DSC thermogram having amelting onset of about 112° C.

Compound 1 Sulfuric Acid Salt or Cocrystal

In some embodiments, Compound 1 can be isolated as a sulfuric acid saltor cocrystal which can be crystalline.

In some embodiments, the crystalline sulfuric acid salt or cocrystal ofCompound 1 has an XRPD profile substantially as shown in FIG. 25.

In some embodiments, the crystalline sulfuric acid salt or cocrystal ofCompound 1 has at least one, at least two, at least three, at leastfour, at least five, at least six, at least seven, at least eight, or atleast nine XRPD peaks, in terms of 2-theta±0.2°, selected from 14.2°,15.3°, 16.3°, 18.3°, 19.1°, 19.3°, 22.6°, 23.9°, and 27.7°.

In some embodiments, the crystalline sulfuric acid salt or cocrystal ofCompound 1 is characterized by a DSC thermogram substantially as shownin FIG. 26.

In some embodiments, the crystalline sulfuric acid salt or cocrystal ofCompound 1 is characterized by a DSC thermogram having a melting onsetof about 169° C.

The present application further provides a process of increasing theamount of an isomeric compound of Isomer A:

relative to an amount of an isomeric compound of Isomer B:

or the amount of an isomeric compound of Isomer B relative to the amountof an isomeric compound of Isomer A, in a starting mixture comprisingboth isomeric compounds, the process comprising:

contacting the starting mixture with an acid or a base in the presenceof a solvent to form a salt mixture of both isomeric compounds, whereinthe salt mixture has an increased amount of the isomeric salt of IsomerA relative to the amount of the isomeric salt of Isomer B, or anincreased amount of the isomeric salt of Isomer B relative to the amountof the isomeric salt of Isomer A, when compared with the relativeamounts of the isomeric compounds of Isomer A and Isomer B in thestarting mixture.

As used herein, the term “contacting” refers to the bringing together ofthe indicated moieties, e.g., in a mixture.

In some embodiments, the process comprises increasing the amount of anisomeric compound of Isomer A relative to an amount of an isomericcompound of Isomer B. In some embodiments, the process of increasing theamount of an isomeric compound of Isomer A relative to an amount of anisomeric compound of Isomer B comprises contacting the starting mixturewith a base in the presence of a solvent.

In some embodiments, the solvent is selected from the group consistingof methanol, ethanol, isopropanol, 1-propanol, acetone, methyl ethylketone, methyl isobutyl ketone, dichloromethane, acetonitrile,2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate,tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, heptane, andwater, or any mixture thereof.

In some embodiments, the process of increasing the amount of an isomericcompound of Isomer A relative to an amount of an isomeric compound ofIsomer B further comprises drying the salt mixture to form a second saltmixture comprising an increased amount of an isomeric compound of IsomerA relative to an amount of an isomeric compound of Isomer B.

In some embodiments, the process comprises increasing the amount of anisomeric compound of Isomer B relative to an amount of an isomericcompound of Isomer A. In some embodiments, the process of increasing theamount of an isomeric compound of Isomer B relative to an amount of anisomeric compound of Isomer A comprises contacting the starting mixturewith a base in the presence of a solvent.

In some embodiments, the solvent is selected from the group consistingof methanol, ethanol, isopropanol, 1-propanol, acetone, methyl ethylketone, methyl isobutyl ketone, dichloromethane, acetonitrile,2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate,tetrahydrofuran, methyl tert-butyl ether, isopropyl ether, heptane, andwater, or any mixture thereof.

In some embodiments, the pharmaceutically acceptable salt, cocrystal, orcrystalline form of Compound 1 disclosed herein is enriched in Isomer A.In some embodiments, the pharmaceutically acceptable salt or crystallineform disclosed herein is enriched in Isomer B. As used herein, the term“enriched,” refers to an increased amount of a particular compound,salt, or isomeric compound in a mixture when compared with the amount ofthe compound, salt, or isomeric compound in the mixture prior to beingenriched. For example, a mixture enriched in an isomeric compound ofIsomer A has an increased amount of the isomeric compound of Isomer Arelative to the isomeric compound of Isomer B when compared with therelative amounts of the isomeric compounds of Isomer A and Isomer B in astarting mixture.

The description below is made with the understanding that the presentdisclosure is to be considered as an exemplification of the claimedsubject matter, and is not intended to limit the appended claims to thespecific embodiments illustrated. The headings used throughout thisdisclosure are provided for convenience and are not to be construed tolimit the claims in any way. Embodiments illustrated under any headingmay be combined with embodiments illustrated under any other heading.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art.

When trade names are used herein, it is intended to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

As used herein and in the appended claims, the singular forms “a” and“an”, and “the” include plural referents unless the context clearlydictates otherwise. Thus, e.g., reference to “the compound” includes aplurality of such compounds and reference to “the assay” includesreference to one or more assays, and so forth.

“Pharmaceutically acceptable” refers to compounds, salts, compositions,dosage forms and other materials which are useful in preparing apharmaceutical composition that is suitable for veterinary or humanpharmaceutical use.

“Pharmaceutically acceptable excipient” includes without limitation anyadjuvant, carrier, excipient, glidant, sweetening agent, diluent,preservative, dye/colorant, flavor enhancer, surfactant, wetting agent,dispersing agent, suspending agent, stabilizer, isotonic agent, solvent,or emulsifier which has been approved by the United States Food and DrugAdministration as being acceptable for use in humans or domesticanimals.

“Pharmaceutically acceptable salt” refers to a salt of a compound thatis pharmaceutically acceptable and that possesses (or can be convertedto a form that possesses) the desired pharmacological activity of theparent compound.

“Subject” and “subjects” refers to humans, domestic animals (e.g., dogsand cats), farm animals (e.g., cattle, horses, sheep, goats and pigs),laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs,rabbits, dogs, and monkeys), and the like.

As used herein, “treatment” or “treating” is an approach for obtainingbeneficial or desired results. For purposes of the present disclosure,beneficial or desired results include, but are not limited to,alleviation of a symptom and/or diminishment of the extent of a symptomand/or preventing a worsening of a symptom associated with a disease orcondition. In one embodiment, “treatment” or “treating” includes one ormore of the following: a) inhibiting the disease or condition (e.g.,decreasing one or more symptoms resulting from the disease or condition,and/or diminishing the extent of the disease or condition); b) slowingor arresting the development of one or more symptoms associated with thedisease or condition (e.g., stabilizing the disease or condition,delaying the worsening or progression of the disease or condition);and/or c) relieving the disease or condition, e.g., causing theregression of clinical symptoms, ameliorating the disease state,delaying the progression of the disease, increasing the quality of life,and/or prolonging survival.

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or subject being treated. Asis evident to one skilled in the art, a sufficient or significant delaycan, in effect, encompass prevention, in that the subject does notdevelop the disease or condition. For example, a method that “delays”development of AIDS is a method that reduces the probability of diseasedevelopment in a given time frame and/or reduces extent of the diseasein a given time frame, when compared to not using the method. Suchcomparisons may be based on clinical studies, using a statisticallysignificant number of subjects. For example, the development of AIDS canbe detected using known methods, such as confirming a subject'sHIV+status and assessing the subject's T-cell count or other indicationof AIDS development, such as extreme fatigue, weight loss, persistentdiarrhea, high fever, swollen lymph nodes in the neck, armpits or groin,or presence of an opportunistic condition that is known to be associatedwith AIDS (e.g., a condition that is generally not present in subjectswith functioning immune systems but does occur in AIDS patients).Development may also refer to disease progression that may be initiallyundetectable and includes occurrence, recurrence and onset.

As used herein, “prevention” or “preventing” refers to a regimen thatprotects against the onset of the disease or disorder such that theclinical symptoms of the disease do not develop. Thus, “prevention”relates to administration of a therapy (e.g., administration of atherapeutic substance) to a subject before signs of the disease aredetectable in the subject (e.g., administration of a therapeuticsubstance to a subject in the absence of detectable infectious agent(e.g., virus) in the subject). The subject may be an individual at riskof developing the disease or disorder, such as an individual who has oneor more risk factors known to be associated with development or onset ofthe disease or disorder. Thus, the term “preventing HIV infection”refers to administering to a subject who does not have a detectable HIVinfection an anti-HIV therapeutic substance. It is understood that thesubject for anti-HIV preventative therapy may be an individual at riskof contracting the HIV virus. Further, it is understood that preventionmay not result in complete protection against onset of the disease ordisorder. In some instances, prevention includes reducing the risk ofdeveloping the disease or disorder. The reduction of the risk may notresult in complete elimination of the risk of developing the disease ordisorder.

As used herein, an “at risk” individual is an individual who is at riskof developing a condition to be treated. An individual “at risk” may ormay not have detectable disease or condition, and may or may not havedisplayed detectable disease prior to the treatment of methods describedherein. “At risk” denotes that an individual has one or more so-calledrisk factors, which are measurable parameters that correlate withdevelopment of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s). For example, individuals at risk for AIDSare those having HIV.

As used herein, the term “therapeutically effective amount” or“effective amount” refers to an amount that is effective to elicit thedesired biological or medical response, including the amount of acompound that, when administered to a subject for treating a disease, issufficient to effect such treatment for the disease or to an amount thatis effective to protect against the contracting or onset of a disease.The effective amount will vary depending on the compound, the disease,and its severity and the age, weight, etc., of the subject to betreated. The effective amount can include a range of amounts. As isunderstood in the art, an effective amount may be in one or more doses,i.e., a single dose or multiple doses may be required to achieve thedesired treatment outcome. An effective amount may be considered in thecontext of administering one or more therapeutic agents, and a singleagent may be considered to be given in an effective amount if, inconjunction with one or more other agents, a desirable or beneficialresult may be or is achieved. Suitable doses of any co-administeredcompounds may optionally be lowered due to the combined action (e.g.,additive or synergistic effects) of the compounds.

“Enantiomers” are a pair of stereoisomers that are non-superimposablemirror images of each other. A 1:1 mixture of a pair of enantiomers is a“racemic” mixture. A mixture of enantiomers at a ratio other than 1:1 isa “scalemic” mixture.

“Diastereoisomers” are stereoisomers that have at least two asymmetricatoms, but which are not mirror-images of each other.

The absolute stereochemistry is specified according to theCahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer thestereochemistry at each chiral carbon may be specified by either R or S.Resolved compounds whose absolute configuration is unknown can bedesignated (+) or (−) depending on the direction (dextro- orlevorotatory) which they rotate plane polarized light at the wavelengthof the sodium D line. Certain of the compounds and salts describedherein contain one or more asymmetric centers and/or hindered rotationabout a bond axis and may thus give rise to enantiomers, diastereomers,and other stereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present disclosure is meant toinclude all such possible isomers, including racemic mixtures, scalemicmixtures, diastereomeric mixtures, optically pure forms and intermediatemixtures. Optically active (R)- and (S)-isomers may be prepared usingchiral synthons or chiral reagents, or resolved using conventionaltechniques.

Except as expressly defined otherwise, the present disclosure includesall tautomers of compounds detailed herein, even if only one tautomer isexpressly represented (e.g., both tautomeric forms are intended anddescribed by the presentation of one tautomeric form where a pair of twotautomers may exist). For example, if reference is made to a compoundcontaining an amide (e.g., by structure or chemical name), it isunderstood that the corresponding imidic acid tautomer is included bythis disclosure and described the same as if the amide were expresslyrecited either alone or together with the imidic acid. Where more thantwo tautomers may exist, the present disclosure includes all suchtautomers even if only a single tautomeric form is depicted by chemicalname and/or structure.

It is understood by one skilled in the art that this disclosure alsoincludes any salt disclosed herein may be enriched at any or all atomsabove naturally occurring isotopic ratios with one or more isotopes suchas, but not limited to, deuterium (²H or D).

Disclosed are also pharmaceutically acceptable salts, cocrystals, andcrystalline forms in which from 1 to n hydrogen atoms attached to acarbon atom may be replaced by a deuterium atom or D, in which n is thenumber of hydrogen atoms in the molecule. As known in the art, thedeuterium atom is a non-radioactive isotope of the hydrogen atom. Suchsalts, cocrystals, and crystalline forms may increase resistance tometabolism, and thus may be useful for increasing the half-life of thecompounds when administered to a mammal. See, e.g., Foster, “DeuteriumIsotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci.,5(12):524-527 (1984). Such salts, cocrystals, and crystalline forms aresynthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogen atoms have beenreplaced by deuterium.

Examples of isotopes that can be incorporated into the disclosed salts,cocrystals, and crystalline forms also include isotopes of hydrogen,carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N , ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively. Substitution with positronemitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful inPositron Emission Topography (PET) studies for examining substratereceptor occupancy. Isotopically-labeled salts can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the Examples as set out belowusing an appropriate isotopically-labeled reagent in place of thenon-labeled reagent previously employed.

Compounds described herein may have chiral centers and/or geometricisomeric centers (E- and Z-isomers), and it is to be understood that allsuch optical, enantiomeric, diastereoisomeric and geometric isomers areencompassed. Where compounds are represented in their chiral form, it isunderstood that the embodiment encompasses, but is not limited to, thespecific diastereomerically or enantiomerically enriched form. Wherechirality is not specified but is present, it is understood that theembodiment is directed to either the specific diastereomerically orenantiomerically enriched form; or a racemic or scalemic mixture of suchcompound(s).

In a preferred embodiment, the current disclosure relates to the use ofthe pharmaceutically acceptable salts, cocrystals, and crystalline formsof the invention in treating a Retroviridae viral infection including aninfection caused by the HIV virus comprising administering atherapeutically effective amount of the pharmaceutically acceptablesalt, cocrystal, or crystalline form to a subject in need thereof.

In a preferred embodiment, the current disclosure relates to the use ofthe pharmaceutically acceptable salts, cocrystals, and crystalline formsof the invention in treating a Retroviridae viral infection including aninfection caused by the HIV virus comprising administering atherapeutically effective amount of the pharmaceutically acceptablesalt, cocrystal, or crystalline form to a subject in need thereof.

It is a desirable goal to discover a compound, a pharmaceuticallyacceptable salt, a cocrystal, or crystalline form thereof having a lowEC₅₀. The EC₅₀ value refers to the concentration of a compound in anassay that achieves 50% of the maximum efficacy. A compound, salt,cocrystal, or crystalline form with a lower EC₅₀ achieves similarefficacy with lower compound, salt, cocrystal, or crystalline formconcentration relative to a compound, salt, cocrystal, or crystallineform with a higher EC₅₀. Thus, a lower EC₅₀ is generally preferred fordrug development.

It is a desirable goal to discover a compound, a pharmaceuticallyacceptable salt, a cocrystal, or crystalline form thereof that has goodphysical and/or chemical stability. An increase in overall stability ofa compound, salt, cocrystal, or crystalline form can provide an increasein circulation time in the body. With less degradation, a stablecompound, salt, cocrystal, or crystalline form can be administered inlower doses and still maintain efficacy. Also, with less degradation,there is less concern about by-products from degradation of a compound,salt, cocrystal, or crystalline form.

It is a desirable goal to discover a compound, a pharmaceuticallyacceptable salt, cocrystal, or crystalline form thereof that hasimproved pharmacokinetic and/or pharmacodynamic profiles and longhalf-life. It is advantageous for a drug to have a moderate or lowclearance and a long half-life, as this can lead to a goodbioavailability and high exposure in systemic exposure. Reducing theclearance and increasing half-life time of a compound, salt, cocrystal,or crystalline form could reduce the daily dose required for efficacyand therefore give a better efficacy and safety profile. Thus, improvedpharmacokinetic and/or pharmacodynamic profiles and long half-life canprovide for better patient compliance.

It is a desirable goal to discover a compound, a pharmaceuticallyacceptable salt, cocrystal, or crystalline form thereof that has goodpharmacokinetic profile from a slow release injectable formulation. Itis advantageous for a drug to have a low EC₅₀ and long actingpharmacokinetics, as this can lead to low frequency of administration.Reducing the frequency of administration can provide for better patientcompliance. Reducing the frequency of administration can be desirablefor patients with difficult or limited access to health care.

Methods of Use

In some embodiments, the pharmaceutically acceptable salts, cocrystals,or crystalline forms disclosed herein are used for preventing an HIVinfection in a subject. In some embodiments, the pharmaceuticallyacceptable salts, cocrystals, or crystalline forms disclosed herein areused for preventing an HIV infection in a subject at risk for infection.In some embodiments, the pharmaceutically acceptable salts, cocrystals,or crystalline forms disclosed herein are used for pre-exposureprophylaxis (PrEP) to reduce the risk of sexually acquired HIV-1. It isbelieved that the pharmaceutically acceptable salts, cocrystals, orcrystalline forms disclosed herein are active against major HIV-1mutants selected by clinical Protease Inhibitors (PIs), nucleosidereverse transcriptase inhibitors (NRTIs), Non-Nucleoside ReverseTranscriptase Inhibitors (NNRTIs), and Integrase inhibitors (INSTIs).

In certain embodiments, a method for treating or preventing an HIVinfection in a subject (e.g., a human), comprising administering apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, to the subject is disclosed.

In some embodiments, a method for treating or preventing an HIVinfection in a subject (e.g., a human), comprising administering apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, to the subject is disclosed.

In certain embodiments, a method for inhibiting the replication of theHIV virus, treating AIDS or delaying the onset of AIDS in a subject(e.g., a human), comprising administering a pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof, to thesubject is disclosed.

In some embodiments, a method for inhibiting the replication of the HIVvirus, treating AIDS or delaying the onset of AIDS in a subject (e.g., ahuman), comprising administering a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, to the subjectis disclosed.

In certain embodiments, a method for preventing an HIV infection in asubject (e.g., a human), comprising administering a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, to the subject is disclosed. In certain embodiments, thesubject is at risk of contracting the HIV virus, such as a subject whohas one or more risk factors known to be associated with contracting theHIV virus.

In some embodiments, a method for preventing an HIV infection in asubject (e.g., a human), comprising administering a therapeuticallyeffective amount of a pharmaceutically acceptable salt of Compound 1, ora cocrystal or crystalline form thereof, to the subject is disclosed. Incertain embodiments, the subject is at risk of contracting the HIVvirus, such as a subject who has one or more risk factors known to beassociated with contracting the HIV virus.

In certain embodiments, a method for treating an HIV infection in asubject (e.g., a human), comprising administering a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, to the subject is disclosed.

In some embodiments, a method for treating an HIV infection in a subject(e.g., a human), comprising administering a pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof, to thesubject is disclosed.

In certain embodiments, a method for treating an HIV infection in asubject (e.g., a human), comprising administering to the subject in needthereof a therapeutically effective amount of a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, in combination with a therapeutically effective amount of oneor more (e.g., one, two, three, or four; or one or two; or one to three;or one to four) additional therapeutic agents selected from the groupconsisting of HIV protease inhibiting compounds, HIV non-nucleosideinhibitors of reverse transcriptase, HIV non-nucleotide inhibitors ofreverse transcriptase, HIV nucleoside inhibitors of reversetranscriptase, HIV nucleotide inhibitors of reverse transcriptase, HIVintegrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120inhibitors, CCR5 inhibitors, capsid polymerization inhibitors,pharmacokinetic enhancers, and other drugs for treating HIV, andcombinations thereof is disclosed. In certain embodiments, a method fortreating an HIV infection in a subject (e.g., a human), comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a pharmaceutically acceptable salt of Compound 1, or acocrystal or crystalline form thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,or four; or one or two; or one to three; or one to four) additionaltherapeutic agents selected from the group consisting of combinationdrugs for HIV, other drugs for treating HIV, HIV protease inhibitors,HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry inhibitors, HIV maturationinhibitors, latency reversing agents, compounds that target the HIVcapsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K)inhibitors, HIV antibodies, bispecific antibodies and “antibody-like”therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13antagonists, peptidyl-prolyl cis-trans isomerase A modulators, proteindisulfide isomerase inhibitors, complement C5a receptor antagonists, DNAmethyltransferase inhibitor, HIV vif gene modulators, Vif dimerizationantagonists, HIV-1 viral infectivity factor inhibitors, TAT proteininhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixedlineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Revprotein inhibitors, integrin antagonists, nucleoprotein inhibitors,splicing factor modulators, COMM domain containing protein 1 modulators,HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, and HIV vaccines, or any combinationsthereof is disclosed. In some embodiments, a method for treating an HIVinfection in a subject (e.g., a human), comprising administering to thesubject in need thereof a therapeutically effective amount of apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, in combination with a therapeuticallyeffective amount of one or more (e.g., one, two, three, or four; or oneor two; or one to three; or one to four) additional therapeutic agentsselected from the group consisting of HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIVnon-nucleotide inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors, pharmacokinetic enhancers, and other drugs for treating HIV,and combinations thereof is disclosed. In certain embodiments, a methodfor treating an HIV infection in a subject (e.g., a human), comprisingadministering to the subject in need thereof a therapeutically effectiveamount of a pharmaceutically acceptable salt of Compound 1, or acocrystal or crystalline form thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,or four; or one or two; or one to three; or one to four) additionaltherapeutic agents selected from the group consisting of combinationdrugs for HIV, other drugs for treating HIV, HIV protease inhibitors,HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry inhibitors, HIV maturationinhibitors, latency reversing agents, compounds that target the HIVcapsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K)inhibitors, HIV antibodies, bispecific antibodies and “antibody-like”therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13antagonists, peptidyl-prolyl cis-trans isomerase A modulators, proteindisulfide isomerase inhibitors, complement C5a receptor antagonists, DNAmethyltransferase inhibitor, HIV vif gene modulators, Vif dimerizationantagonists, HIV-1 viral infectivity factor inhibitors, TAT proteininhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixedlineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Revprotein inhibitors, integrin antagonists, nucleoprotein inhibitors,splicing factor modulators, COMM domain containing protein 1 modulators,HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, and HIV vaccines, or any combinationsthereof is disclosed.

In certain embodiments, a method for treating an HIV infection in asubject (e.g., a human), comprising administering to the subject in needthereof a therapeutically effective amount of a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, in combination with a therapeutically effective amount of oneor more (e.g., one, two, three, or four; or one or two; or one to three;or one to four) additional therapeutic agents selected from the groupconsisting of combination drugs for HIV, other drugs for treating HIV,HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitorsof reverse transcriptase, HIV nucleoside or nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site(or allosteric) integrase inhibitors, and HIV nucleoside reversetranscriptase translocation inhibitors.

In certain embodiments, a pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, for use in medicaltherapy of an HIV infection (e.g. HIV-1 or the replication of the HIVvirus (e.g. HIV-1) or AIDS or delaying the onset of AIDS in a subject(e.g., a human)) is disclosed.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, for use in medical therapyof an HIV infection (e.g. HIV-1 or the replication of the HIV virus(e.g. HIV-1) or AIDS or delaying the onset of AIDS in a subject (e.g., ahuman)) is disclosed.

In certain embodiments, a pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, for use in themanufacture of a medicament for treating an HIV infection or thereplication of the HIV virus or AIDS or delaying the onset of AIDS in asubject (e.g., a human) is disclosed. One embodiment relates to apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, for use in the prophylactic or therapeutictreatment of an HIV infection or AIDS or for use in the therapeutictreatment or delaying the onset of AIDS.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof for use in the manufacture ofa medicament for treating an HIV infection or the replication of the HIVvirus or AIDS or delaying the onset of AIDS in a subject (e.g., a human)is disclosed. One embodiment relates to a pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof, for usein the prophylactic or therapeutic treatment of an HIV infection or AIDSor for use in the therapeutic treatment or delaying the onset of AIDS.

In certain embodiments, the use of a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, for themanufacture of a medicament for an HIV infection in a subject (e.g., ahuman) is disclosed. In certain embodiments, a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, for use in the prophylactic or therapeutic treatment of an HIVinfection is disclosed.

In some embodiments, the use of a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, for themanufacture of a medicament for an HIV infection in a subject (e.g., ahuman) is disclosed. In certain embodiments, a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, for use in the prophylactic or therapeutic treatment of an HIVinfection is disclosed.

In certain embodiments, in the methods of use, the administration is toa subject (e.g., a human) in need of the treatment. In certainembodiments, in the methods of use, the administration is to a subject(e.g., a human) who is at risk of developing AIDS.

Disclosed herein is a pharmaceutically acceptable salt of Compound 1, ora cocrystal or crystalline form thereof, for use in therapy. In oneembodiment, the pharmaceutically acceptable salt of Compound 1, or acocrystal or crystalline form thereof, is for use in a method oftreating an HIV infection or the replication of the HIV virus or AIDS ordelaying the onset of AIDS in a subject (e.g., a human).

In some embodiments, disclosed herein is a pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof, for usein therapy. In some embodiments, the pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, is for use in amethod of treating an HIV infection or the replication of the HIV virusor AIDS or delaying the onset of AIDS in a subject (e.g., a human).

Also disclosed herein is a pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, for use in a method oftreating or preventing HIV infection in a subject in need thereof. Incertain embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, for use in a method oftreating HIV infection in a subject in need thereof is provided. Incertain embodiments, the subject in need thereof is a human who has beeninfected with HIV. In certain embodiments, the subject in need thereofis a human who has been infected with HIV but who has not developedAIDS. In certain embodiments, the subject in need thereof is a subjectat risk for developing AIDS. In certain embodiments, the subject in needthereof is a human who has been infected with HIV and who has developedAIDS.

In some embodiments, disclosed herein is a pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof, for usein a method of treating or preventing HIV infection in a subject in needthereof. In certain embodiments, a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, for use in amethod of treating HIV infection in a subject in need thereof isprovided. In certain embodiments, the subject in need thereof is a humanwho has been infected with HIV. In certain embodiments, the subject inneed thereof is a human who has been infected with HIV but who has notdeveloped AIDS. In certain embodiments, the subject in need thereof is asubject at risk for developing AIDS. In certain embodiments, the subjectin need thereof is a human who has been infected with HIV and who hasdeveloped AIDS.

In one embodiment, a pharmaceutically acceptable salt of Compound 1, ora cocrystal or crystalline form thereof, in combination with one or more(e.g. one, two, three, or four; or one or two; or one to three; or oneto four) additional therapeutic agents as described herein for use in amethod of treating or preventing HIV infection in a subject in needthereof is provided. In one embodiment, said additional therapeuticagents are selected from the group consisting of combination drugs forHIV, other drugs for treating HIV, HIV protease inhibitors, HIVnon-nucleoside or non-nucleotide inhibitors of reverse transcriptase,HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIVintegrase inhibitors, HIV non-catalytic site (or allosteric) integraseinhibitors, HIV entry inhibitors, HIV maturation inhibitors, latencyreversing agents, compounds that target the HIV capsid, immune-basedtherapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIVantibodies, bispecific antibodies and “antibody-like” therapeuticproteins, HIV p17 matrix protein inhibitors, IL-13 antagonists,peptidyl-prolyl cis-trans isomerase A modulators, protein disulfideisomerase inhibitors, complement C5a receptor antagonists, DNAmethyltransferase inhibitor, HIV vif gene modulators, Vif dimerizationantagonists, HIV-1 viral infectivity factor inhibitors, TAT proteininhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixedlineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Revprotein inhibitors, integrin antagonists, nucleoprotein inhibitors,splicing factor modulators, COMM domain containing protein 1 modulators,HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, and HIV vaccines, or any combinationsthereof. In one embodiment, said additional therapeutic agents areselected from the group consisting of HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIVnon-nucleotide inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors, pharmacokinetic enhancers, and other drugs for treating HIV,and combinations thereof.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, in combination with one ormore (e.g. one, two, three, or four; or one or two; or one to three; orone to four) additional therapeutic agents as described herein for usein a method of treating or preventing HIV infection in a subject in needthereof is provided. In one embodiment, said additional therapeuticagents are selected from the group consisting of combination drugs forHIV, other drugs for treating HIV, HIV protease inhibitors, HIVnon-nucleoside or non-nucleotide inhibitors of reverse transcriptase,HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIVintegrase inhibitors, HIV non-catalytic site (or allosteric) integraseinhibitors, HIV entry inhibitors, HIV maturation inhibitors, latencyreversing agents, compounds that target the HIV capsid, immune-basedtherapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIVantibodies, bispecific antibodies and “antibody-like” therapeuticproteins, HIV p17 matrix protein inhibitors, IL-13 antagonists,peptidyl-prolyl cis-trans isomerase A modulators, protein disulfideisomerase inhibitors, complement C5a receptor antagonists, DNAmethyltransferase inhibitor, HIV vif gene modulators, Vif dimerizationantagonists, HIV-1 viral infectivity factor inhibitors, TAT proteininhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixedlineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Revprotein inhibitors, integrin antagonists, nucleoprotein inhibitors,splicing factor modulators, COMM domain containing protein 1 modulators,HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, and HIV vaccines, or any combinationsthereof. In one embodiment, said additional therapeutic agents areselected from the group consisting of HIV protease inhibiting compounds,HIV non-nucleoside inhibitors of reverse transcriptase, HIVnon-nucleotide inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerizationinhibitors, pharmacokinetic enhancers, and other drugs for treating HIV,and combinations thereof.

In one embodiment, a pharmaceutically acceptable salt of Compound 1, ora cocrystal or crystalline form thereof, in combination with a firstadditional therapeutic agent selected from the group consisting oftenofovir alafenamide fumarate, tenofovir alafenamide, and tenofoviralafenamide hemifumarate, and a second additional therapeutic agent,wherein the second additional therapeutic agent is emtricitabine, isprovided for use in a method of treating or preventing HIV infection ina subject in need thereof. In a particular embodiment, apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, in combination with a first additionaltherapeutic agent selected from the group consisting of tenofovirdisoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxilhemifumarate, and a second additional therapeutic agent, wherein thesecond additional therapeutic agent is emtricitabine, is provided foruse in a method of treating or preventing HIV infection in a subject inneed thereof.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, in combination with a firstadditional therapeutic agent selected from the group consisting oftenofovir alafenamide fumarate, tenofovir alafenamide, and tenofoviralafenamide hemifumarate, and a second additional therapeutic agent,wherein the second additional therapeutic agent is emtricitabine, isprovided for use in a method of treating or preventing HIV infection ina subject in need thereof. In a particular embodiment, apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, in combination with a first additionaltherapeutic agent selected from the group consisting of tenofovirdisoproxil fumarate, tenofovir disoproxil, and tenofovir disoproxilhemifumarate, and a second additional therapeutic agent, wherein thesecond additional therapeutic agent is emtricitabine, is provided foruse in a method of treating or preventing HIV infection in a subject inneed thereof.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, is provided in combinationwith at least one additional therapeutic agent selected from the groupconsisting of:

-   -   (1) nucleoside reverse transcriptase translocation inhibitors        (“NRTTIs”), such as 4′-Ethynyl-2-fluoro-2′-deoxyadenosine        triphosphate (also known as MK-8591 and EFdA);    -   (2) nucleoside or nucleotide reverse transcriptase inhibitors        (“NRTIs”), such as tenofovir alafenamide fumarate, tenofovir        alafenamide, tenofovir alafenamide hemifumarate, GS-9131, and        GS-9148;    -   (3) non-nucleoside or non-nucleotide reverse transcriptase        inhibitors (“NNRTIs”), such as efavirenz, etravirine,        rilpivirine, nevirapine, and delavirdine;    -   (4) protease Inhibitors (“PIs”), such as amprenavir, atazanavir,        brecanavir, darunavir, fosamprenavir, fosamprenavir calcium,        indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir        mesylate, ritonavir, saquinavir, saquinavir mesylate,        tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, and        TMC-31091; and    -   (5) integrase strand transfer inhibitors (“INSTIs”), such as        Bictegravir, cabotegravir, raltegravir, and dolutegravir.

In a particular embodiment, a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, is provided foruse to prevent HIV infection from taking hold if the individual isexposed to the virus and/or to keep the virus from establishing apermanent infection and/or to prevent the appearance of symptoms of thedisease and/or to prevent the virus from reaching detectable levels inthe blood, for example for pre-exposure prophylaxis (PrEP) orpost-exposure prophylaxis (PEP). Accordingly, in certain embodiments,methods for reducing the risk of acquiring HIV (e.g., HIV-1 and/orHIV-2) are provided. For example, methods for reducing the risk ofacquiring HIV (e.g., HIV-1 and/or HIV-2) comprise administration of apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof. In certain embodiments, methods for reducingthe risk of acquiring HIV (e.g., HIV-1 and/or HIV-2) compriseadministration of a pharmaceutically acceptable salt of Compound 1, or acocrystal or crystalline form thereof, in combination with one or moreadditional therapeutic agents. In certain embodiments, methods forreducing the risk of acquiring HIV (e.g., HIV-1 and/or HIV-2) compriseadministration of a pharmaceutical composition comprising atherapeutically effective amount of a pharmaceutically acceptable saltof Compound 1, or a cocrystal or crystalline form thereof, and apharmaceutically acceptable excipient.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, is provided for use toprevent HIV infection from taking hold if the individual is exposed tothe virus and/or to keep the virus from establishing a permanentinfection and/or to prevent the appearance of symptoms of the diseaseand/or to prevent the virus from reaching detectable levels in theblood, for example for pre-exposure prophylaxis (PrEP) or post-exposureprophylaxis (PEP). Accordingly, in certain embodiments, methods forreducing the risk of acquiring HIV (e.g., HIV-1 and/or HIV-2) areprovided. For example, methods for reducing the risk of acquiring HIV(e.g., HIV-1 and/or HIV-2) comprise administration of a pharmaceuticallyacceptable salt of Compound 1, or crystalline form thereof. In certainembodiments, methods for reducing the risk of acquiring HIV (e.g., HIV-1and/or HIV-2) comprise administration of a pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof, incombination with one or more additional therapeutic agents. In certainembodiments, methods for reducing the risk of acquiring HIV (e.g., HIV-1and/or HIV-2) comprise administration of a pharmaceutical compositioncomprising a therapeutically effective amount of a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, and a pharmaceutically acceptable excipient.

In certain embodiments, methods for reducing the risk of acquiring HIV(e.g., HIV-1 and/or HIV-2) comprise administration of a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, in combination with safer sex practices. In certainembodiments, methods for reducing the risk of acquiring HIV (e.g., HIV-1and/or HIV-2) comprise administration to an individual at risk ofacquiring HIV. Examples of individuals at high risk for acquiring HIVinclude, without limitation, an individual who is at risk of sexualtransmission of HIV.

In some embodiments, methods for reducing the risk of acquiring HIV(e.g., HIV-1 and/or HIV-2) comprise administration of a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, in combination with safer sex practices. In certainembodiments, methods for reducing the risk of acquiring HIV (e.g., HIV-1and/or HIV-2) comprise administration to an individual at risk ofacquiring HIV. Examples of individuals at high risk for acquiring HIVinclude, without limitation, an individual who is at risk of sexualtransmission of HIV.

In certain embodiments, the reduction in risk of acquiring HIV is atleast about 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In certainembodiments, the reduction in risk of acquiring HIV is at least about75%. In certain embodiments, the reduction in risk of acquiring HIV isabout 80%, 85%, or 90%.

In another embodiment, the use of a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, for themanufacture of a medicament for the treatment of an HIV infection in ahuman being having or at risk of having the infection is disclosed.

In some embodiments, the use of a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, for themanufacture of a medicament for the treatment of an HIV infection in ahuman being having or at risk of having the infection is disclosed.

Also disclosed herein is a pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, for use in thetherapeutic treatment or delaying the onset of AIDS.

In some embodiments, disclosed herein is a pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof, for usein the therapeutic treatment or delaying the onset of AIDS.

Also disclosed herein is a pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, for use in theprophylactic or therapeutic treatment of an HIV infection.

In some embodiments, disclosed herein is a pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof, for usein the prophylactic or therapeutic treatment of an HIV infection.

In certain embodiments, a pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, can be used as a researchtool.

Routes of Administration

The pharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, (also referred to herein as the activeingredient) can be administered by any route appropriate to thecondition to be treated. Suitable routes include oral, rectal, nasal,topical (including buccal and sublingual), transdermal, vaginal andparenteral (including subcutaneous, intramuscular, intravenous,intradermal, intrathecal and epidural), and the like. It will beappreciated that the preferred route may vary with, for example, thecondition of the recipient. In certain embodiments, the compounds,salts, cocrystals, or crystalline forms disclosed can be dosedparenterally. In certain embodiments, the compounds, salts, cocrystals,or crystalline forms disclosed can be dosed intravenous, subcutaneous,or intramuscular. In certain embodiments, the compounds, salts,cocrystals, and crystalline forms disclosed are orally bioavailable andcan be dosed orally.

In some embodiments, the pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, may be administered with asyringe suitable for administration of the compound. In someembodiments, the syringe is disposable. In some embodiments, the syringeis reusable. In some embodiments, the syringe is pre-filled with thepharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof.

In some embodiments, the pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, may be administered viainjection, using an injection device. In some embodiments, the injectiondevice is or includes a syringe, which can be employed manually, or aspart of a syringe-containing injection device, such as, but not limitedto, one with a needle safety shield. A wide variety of injection devicescan be used, such as, for example and not limited to, a handheld orwearable autoinjector, a handheld or wearable manual injector, anon-body injector, a syrette, a jet injector, or a pen injector, each ofwhich can be reusable or disposable.

In some embodiments, the pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, may be administered with anauto-injector comprising a syringe. In some embodiments, the syringe isdisposable. In some embodiments, the syringe is reusable. In someembodiments, the syringe is pre-filled with the pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof.

Dosing Regimen

The pharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, may be administered to a subject in accordancewith an effective dosing regimen for a desired period of time orduration, such as at least about one day, at least about one week, atleast about one month, at least about 2 months, at least about 3 months,at least about 4 months, at least about 6 months, or at least about 12months or longer. In one variation, the salt, cocrystal, or crystallineform is administered on a daily or intermittent schedule. In onevariation, the salt, cocrystal, or crystalline form is administered on amonthly schedule. In one variation, the salt, cocrystal, or crystallineform is administered every two months. In one variation, the salt,cocrystal, or crystalline form is administered every three months. Inone variation, the salt, cocrystal, or crystalline form is administeredevery four months. In one variation, the salt, cocrystal, or crystallineform is administered every five months. In one variation, the salt,cocrystal, or crystalline form is administered every 6 months.

In some embodiments, the pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, may be administered to asubject at least about one month, at least about 4 months, or at leastabout 6 months. In some embodiments, the pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof, may besubcutaneously administered to a subject at least about one month. Insome embodiments, the pharmaceutically acceptable salt of Compound 1, ora cocrystal or crystalline form thereof, may be subcutaneously orintramuscularly administered to a subject at least about 4 months, or atleast about 6 months.

The dosage or dosing frequency of the pharmaceutically acceptable saltof Compound 1, or a cocrystal or crystalline form thereof, may beadjusted over the course of the treatment, based on the judgment of theadministering physician.

In some embodiments, the dosage or dosing frequency of thepharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, may be adjusted over the course of thetreatment, based on the judgment of the administering physician.

The pharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof may be administered to a subject (e.g., ahuman) in an effective amount. In certain embodiments, thepharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof is administered once daily.

In some embodiments, the pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, may be administered to asubject (e.g., a human) in an therapeutically effective amount. In someembodiments, the pharmaceutically acceptable salt of Compound 1, or acocrystal or crystalline form thereof, is administered once daily. Insome embodiments, the pharmaceutically acceptable salt of Compound 1, ora cocrystal or crystalline form thereof, is administered monthly. Insome embodiments, the pharmaceutically acceptable salt of Compound 1, ora cocrystal or crystalline form thereof, is administered every threemonths. In some embodiments, the pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, is administeredevery four months. In some embodiments, the pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof, isadministered every six months.

A pharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein may be administered in adosage amount that is effective. For example, the dosage amount can befrom 1 mg to 1000 mg of compound. In certain embodiments, the dosageamount is about 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 100, 105,110, 120, 130, 140, or 150 mg of compound. In certain embodiments thedosage amount is about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550,600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg.

In some embodiments, the pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, is administered in a oncedaily dose. In some embodiments, the pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, is administeredin a once daily dose of about 1 mg.

In some embodiments, the pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, is administered monthly. Insome embodiments, the pharmaceutically acceptable salt of Compound 1, ora cocrystal or crystalline form thereof, is administered monthly at adose of about 100 mg.

In some embodiments, the pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, is administered every 6months. In some embodiments, the pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, is administeredevery 6 months at a dose of about 600 mg.

Combination Therapies

In certain embodiments, a method for treating or preventing an HIVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a pharmaceutically acceptable salt of Compound 1, ora cocrystal or crystalline form thereof, disclosed herein in combinationwith a therapeutically effective amount of one or more (e.g., one, two,three, or four; or one or two; or one to three; or one to four)additional therapeutic agents. In one embodiment, a method for treatingan HIV infection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a pharmaceutically acceptable salt of Compound 1, ora cocrystal or crystalline form thereof, disclosed herein in combinationwith a therapeutically effective amount of one or more (e.g., one, two,three, or four; or one or two; or one to three; or one to four)additional therapeutic agents.

In some embodiments, a method for treating or preventing an HIVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a pharmaceutically acceptable salt of Compound 1, ora cocrystal or crystalline form thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,or four; or one or two; or one to three; or one to four) additionaltherapeutic agents. In one embodiment, a method for treating an HIVinfection in a human having or at risk of having the infection isprovided, comprising administering to the human a therapeuticallyeffective amount of a pharmaceutically acceptable salt of Compound 1, ora cocrystal or crystalline form thereof, in combination with atherapeutically effective amount of one or more (e.g., one, two, three,or four; or one or two; or one to three; or one to four) additionaltherapeutic agents.

In one embodiment, pharmaceutical compositions comprising apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, in combination with one or more (e.g., one,two, three, or four; or one or two; or one to three; or one to four)additional therapeutic agents, and a pharmaceutically acceptableexcipient are provided.

In some embodiments, pharmaceutical compositions comprising apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, in combination with one or more (e.g., one,two, three, or four; or one or two; or one to three; or one to four)additional therapeutic agents, and a pharmaceutically acceptableexcipient are provided.

In certain embodiments, the present disclosure provides a method fortreating an HIV infection, comprising administering to a subject in needthereof a therapeutically effective amount of a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, in combination with a therapeutically effective amount of oneor more additional therapeutic agents which are suitable for treating anHIV infection.

In certain embodiments, the present disclosure provides a method fortreating an HIV infection, comprising administering to a subject in needthereof a therapeutically effective amount of a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, in combination with a therapeutically effective amount of oneor more additional therapeutic agents which are suitable for treating anHIV infection.

In certain embodiments, a pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, disclosed herein iscombined with one, two, three, four, or more additional therapeuticagents. In certain embodiments, a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, disclosed hereinis combined with one additional therapeutic agent. In certainembodiments, a pharmaceutically acceptable salt of Compound 1, or acocrystal or crystalline form thereof, disclosed herein is combined withtwo additional therapeutic agents. In other embodiments, apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein is combined with threeadditional therapeutic agents. In further embodiments, apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein is combined with fouradditional therapeutic agents. The one, two, three, four, or moreadditional therapeutic agents can be different therapeutic agentsselected from the same class of therapeutic agents, and/or they can beselected from different classes of therapeutic agents.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein is combinedwith one, two, three, four, or more additional therapeutic agents. Incertain embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein is combinedwith one additional therapeutic agent. In certain embodiments, apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein is combined with twoadditional therapeutic agents. In other embodiments, a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, disclosed herein is combined with three additional therapeuticagents. In further embodiments, a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, disclosed hereinis combined with four additional therapeutic agents. The one, two,three, four, or more additional therapeutic agents can be differenttherapeutic agents selected from the same class of therapeutic agents,and/or they can be selected from different classes of therapeuticagents.

Administration of HIV Combination Therapy

In certain embodiments, a pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, disclosed herein isadministered with one or more additional therapeutic agents.Co-administration of a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein with one ormore additional therapeutic agents generally refers to simultaneous orsequential administration of a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, and one or moreadditional therapeutic agents, such that therapeutically effectiveamounts of the pharmaceutically acceptable salt of Compound 1, or acocrystal or crystalline form thereof, and the one or more additionaltherapeutic agents are both present in the body of the subject. Whenadministered sequentially, the combination may be administered in two ormore administrations.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein isadministered with one or more additional therapeutic agents.Co-administration of a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein with one ormore additional therapeutic agents generally refers to simultaneous orsequential administration of the pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, and one or moreadditional therapeutic agents, such that therapeutically effectiveamounts of the a pharmaceutically acceptable salt of Compound 1, or acocrystal or crystalline form thereof, and the one or more additionaltherapeutic agents are both present in the body of the subject. Whenadministered sequentially, the combination may be administered in two ormore administrations.

Co-administration includes administration of unit dosages of thepharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, before or after administration of unit dosagesof one or more additional therapeutic agents. For example, thepharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, may be administered within seconds, minutes,or hours of the administration of the one or more additional therapeuticagents. In some embodiments, a unit dose of a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, is administered first, followed within seconds or minutes byadministration of a unit dose of one or more additional therapeuticagents. Alternatively, a unit dose of one or more additional therapeuticagents is administered first, followed by administration of a unit doseof a pharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, within seconds or minutes. In otherembodiments, a unit dose of a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, is administeredfirst, followed, after a period of hours (e.g., 1-12 hours), byadministration of a unit dose of one or more additional therapeuticagents. In yet other embodiments, a unit dose of one or more additionaltherapeutic agents is administered first, followed, after a period ofhours (e.g., 1-12 hours), by administration of a unit dose of apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof.

In certain embodiments, a pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, disclosed herein iscombined with one or more additional therapeutic agents in a unitarydosage form for simultaneous administration to a subject. In certainembodiments, such a unitary dosage form can be administered by any routeappropriate to the condition to be treated. Suitable routes includeoral, rectal, nasal, topical (including buccal and sublingual),transdermal, vaginal and parenteral (including subcutaneous,intramuscular, intravenous, intradermal, intrathecal and epidural), andthe like. In certain embodiments, the compounds disclosed can be dosedparenterally. In certain embodiments, the unitary dosage form can bedosed intravenous, subcutaneous, or intramuscular. In certainembodiments, the unitary dosage form is orally bioavailable and can bedosed orally. In certain embodiments, the unitary dosage form can be asolid dosage form for oral administration.

The pharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein in combination with one ormore additional therapeutic agents can be administered by any routeappropriate to the condition to be treated. Suitable routes includeoral, rectal, nasal, topical (including buccal and sublingual),transdermal, vaginal and parenteral (including subcutaneous,intramuscular, intravenous, intradermal, intrathecal and epidural), andthe like. In certain embodiments, the pharmaceutically acceptable saltof Compound 1, or a cocrystal or crystalline form thereof, disclosedherein can be dosed parenterally. In certain embodiments, thepharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein can be dosed intravenous,subcutaneous, or intramuscular. In certain embodiments, thepharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein are orally bioavailable andcan be dosed orally.

In certain embodiments, a pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, disclosed herein isformulated as a tablet, which may optionally contain one or more othercompounds useful for treating HIV. In certain embodiments, the tabletcan one or more other compounds useful for treating HIV, such as HIVprotease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors ofreverse transcriptase, HIV nucleoside or nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site(or allosteric) integrase inhibitors, pharmacokinetic enhancers, andcombinations thereof.

In certain embodiments, a pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, disclosed herein isformulated as a tablet, which may optionally contain one or more othercompounds useful for treating HIV. In certain embodiments, the tabletcan one or more other compounds useful for treating HIV, such as HIVnucleoside reverse transcriptase translocation inhibitors, HIV proteaseinhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, pharmacokinetic enhancers, andcombinations thereof.

In certain embodiments, such tablets are suitable for once daily dosing.

HIV Combination Therapy

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein isadministered with at least one additional therapeutic agent.

In the above embodiments, the additional therapeutic agent may be ananti-HIV agent selected from the group consisting of combination drugsfor treating HIV, other drugs for treating HIV, HIV protease inhibitors,HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase, HIV nucleoside or nucleotide inhibitors of reversetranscriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry inhibitors, HIV maturationinhibitors, latency reversing agents, compounds that target the HIVcapsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K)inhibitors, HIV antibodies, bispecific antibodies and “antibody-like”therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13antagonists, peptidyl-prolyl cis-trans isomerase A modulators, proteindisulfide isomerase inhibitors, complement C5a receptor antagonists, DNAmethyltransferase inhibitor, HIV vif gene modulators, Vif dimerizationantagonists, HIV-1 viral infectivity factor inhibitors, TAT proteininhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixedlineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Revprotein inhibitors, integrin antagonists, nucleoprotein inhibitors,splicing factor modulators, COMM domain containing protein 1 modulators,HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors,dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG proteininhibitors, HIV POL protein inhibitors, Complement Factor H modulators,ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclindependent kinase inhibitors, proprotein convertase PC9 stimulators, ATPdependent RNA helicase DDX3X inhibitors, reverse transcriptase primingcomplex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokineticenhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of combination drugs for HIV, other drugs fortreating HIV, HIV protease inhibitors, HIV reverse transcriptaseinhibitors, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIVmaturation inhibitors, latency reversing agents, capsid inhibitors,immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecificantibodies, and “antibody-like” therapeutic proteins, and combinationsthereof.

In some embodiments, the additional therapeutic agent is selected fromthe group consisting of combination drugs for HIV, other drugs fortreating HIV, HIV nucleoside reverse transcriptase translocationinhibitors, HIV protease inhibitors, HIV reverse transcriptaseinhibitors, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIVmaturation inhibitors, latency reversing agents, capsid inhibitors,immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecificantibodies, and “antibody-like” therapeutic proteins, and combinationsthereof. In some embodiments, the additional therapeutic agent isselected from immunomodulators, immunotherapeutic agents, antibody-drugconjugates, gene modifiers, gene editors (such as CRISPR/Cas9, zincfinger nucleases, homing nucleases, synthetic nucleases, TALENs), andcell therapies such as chimeric antigen receptor T-cell, CAR-T (e.g.,YESCARTA® (axicabtagene ciloleucel)), and engineered T cell receptors,TCR-T.

HIV Combination Drugs

Examples of combination drugs include ATRIPLA® (efavirenz, tenofovirdisoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®;rilpivirine, tenofovir disoproxil fumarate, and emtricitabine);STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, andemtricitabine); TRUVADA® (tenofovir disoproxil fumarate andemtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide andemtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); darunavir, tenofovir alafenamidehemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, andtenofovir disoproxil fumarate; lamivudine and tenofovir disoproxilfumarate; tenofovir and lamivudine; tenofovir alafenamide andemtricitabine; tenofovir alafenamide hemifumarate and emtricitabine;tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine;tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, andelvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM®(LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®;lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, andlamivudine); TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine;ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate andcobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat;dolutegravir and rilpivirine; dolutegravir and rilpivirinehydrochloride; cabotegravir and rilpivirine; cabotegravir andrilpivirine hydrochloride; dolutegravir, abacavir sulfate, andlamivudine; lamivudine, nevirapine, and zidovudine; raltegravir andlamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate;doravirine, lamivudine, and tenofovir disoproxil;dolutegravir+lamivudine; lamivudine+abacavir+zidovudine;lamivudine+abacavir; lamivudine+tenofovir disoproxil fumarate;lamivudine+zidovudine+nevirapine; lopinavir+ritonavir;lopinavir+ritonavir+abacavir+lamivudine;lopinavir+ritonavir+zidovudine+lamivudine; tenofovir+lamivudine; andtenofovir disoproxil fumarate+emtricitabine+rilpivirine hydrochloride;lopinavir , ritonavir, zidovudine and lamivudine; Vacc-4x andromidepsin; and APH-0812.

Other HIV Drugs

Examples of other drugs for treating HIV include acemannan, alisporivir,BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP9, RPI-MN, VSSP, Hlviral, SB-728-T, 1,5-dicaffeoylquinic acid,rHIV7-shl-TAR-CCRSRZ, AAV-eCD4-Ig gene therapy, MazF gene therapy,BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43,HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205,PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452,TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

HIV Nucleoside Reverse Transcriptase Translocation Inhibitors

Examples of HIV nucleoside reverse transcriptase translocationinhibitors (“NRTTIs”) include 4′-Ethynyl-2-fluoro-2′-deoxyadenosinetriphosphate (also known as MK-8591 and EFdA).

HIV Protease Inhibitors

Examples of HIV protease inhibitors include amprenavir, atazanavir,brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir,indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate,ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657(PPL-100), T-169, BL-008, and TMC-310911.

HIV Reverse Transcriptase Inhibitors

Examples of HIV non-nucleoside or non-nucleotide inhibitors of reversetranscriptase include dapivirine, delavirdine, delavirdine mesylate,doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine,AIC-292, KM-023, and VM-1500. Further examples of non-nucleoside reversetranscriptase inhibitors are disclosed in U.S. Patent Publication No.US2016/0250215.

Examples of HIV nucleoside or nucleotide inhibitors of reversetranscriptase include adefovir, adefovir dipivoxil, azvudine,emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil,tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®and VIDEX EC® (didanosine, dd1), abacavir, abacavir sulfate, alovudine,apricitabine, censavudine, didanosine, elvucitabine, festinavir,fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine,OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine,phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, andKP-1461.

In some embodiments, examples of HIV nucleoside or nucleotide inhibitorsof reverse transcriptase include adefovir, adefovir dipivoxil, azvudine,emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamidefumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil,tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®and VIDEX EC® (didanosine, dd1), abacavir, abacavir sulfate, alovudine,apricitabine, censavudine, didanosine, elvucitabine, festinavir,fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine,OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine,phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148,KP-1461, and 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA).

HIV Integrase Inhibitors

Examples of HIV integrase inhibitors include elvitegravir, curcumin,derivatives of curcumin, chicoric acid, derivatives of chicoric acid,3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid,aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeicacid phenethyl ester, derivatives of caffeic acid phenethyl ester,tyrphostin, derivatives of tyrphostin, quercetin, derivatives ofquercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567,diketo quinolin-4-1 derivatives, integrase-LEDGF inhibitor, ledgins,M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171,NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T-169 andcabotegravir.

Examples of HIV non-catalytic site, or allosteric, integrase inhibitors(NCINI) include CX-05045, CX-05168, and CX-14442.

HIV Entry Inhibitors

Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCRSinhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120inhibitors, and CXCR4 inhibitors.

Examples of CCRS inhibitors include aplaviroc, vicriviroc, maraviroc,cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232),anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptideC25P, TD-0680, and vMIP Haimipu).

Examples of gp41 inhibitors include albuvirtide, enfuvirtide,BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusioninhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer andsifuvirtide.

Examples of CD4 attachment inhibitors include ibalizumab and CADAanalogs

Examples of gp120 inhibitors include Radha-108 (receptol) 3B3-PE38,BanLec, bentonite-based nanomedicine, fostemsavir tromethamine,IQP-0831, and BMS-663068

Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide,and vMIP (Haimipu).

HIV Maturation Inhibitors

Examples of HIV maturation inhibitors include BMS-955176 andGSK-2838232.

Latency Reversing Agents

Examples of latency reversing agents include histone deacetylase (HDAC)inhibitors, proteasome inhibitors such as velcade, protein kinase C(PKC) activators, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA,SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamicacid), IL-15, JQ1, disulfram, amphotericin B, and ubiquitin inhibitorssuch as largazole analogs, and GSK-343.

Examples of HDAC inhibitors include romidepsin, vorinostat, andpanobinostat.

Examples of PKC activators include indolactam, prostratin, ingenol B,and DAG-lactones.

Capsid Inhibitors

Examples of capsid inhibitors include capsid polymerization inhibitorsor capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitorssuch as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621,AVI-101, AVI-201, AVI-301, and AVI-CANT-15 series.

Immune-Based Therapies

Examples of immune-based therapies include toll-like receptorsmodulators such as t1r1, t1r2, t1r3, t1r4, t1r5, t1r6, t1r7, t1r8, t1r9,t1r10, t1r11, t1r12, and t1r13; programmed cell death protein 1 (Pd-1)modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15agonists; DermaVir; interleukin-7; plaquenil (hydroxychloroquine);proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b;interferon alfa-n3; pegylated interferon alfa; interferon gamma;hydroxyurea; mycophenolate mofetil (MPA) and its ester derivativemycophenolate mofetil (MMF); ribavirin; rintatolimod, polymerpolyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1;MOR-22; BMS-936559; CYT-107, interleukin-15/Fc fusion protein,normferon, peginterferon alfa-2a, peginterferon alfa-2b, recombinantinterleukin-15, RPI-MN, GS-9620, and IR-103.

Phosphatidylinositol 3-Kinase (PI3K) Inhibitors

Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib,CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib,perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib,rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439,CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577,GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666,RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857,VS-5584, XL-765, and ZSTK-474.

HIV Antibodies, Bispecific Antibodies, and “Antibody-Like” TherapeuticProteins

Examples of HIV antibodies, bispecific antibodies, and “antibody-like”therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®,TandAbs®, Fab derivatives, bnABs (broadly neutralizing HIV-1antibodies), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41,antibody-Recruiting Molecules targeting HIV, anti-CD63 monoclonalantibodies , anti-GB virus C antibodies, anti-GP120/CD4, CCRS bispecificantibodies, anti-nef single domain antibodies, anti-Rev antibody,camelid derived anti-CD18 antibodies, camelid-derived anti-ICAM-1antibodies, DCVax-001, gp140 targeted antibodies, gp41-based HIVtherapeutic antibodies, human recombinant mAbs (PGT-121), ibalizumab,Immuglo, MB-66.

Examples of those targeting HIV in such a manner include bavituximab,UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, PGT145, PGT121,MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8, VRC-07-523,VRC-HIVMAB080-00-AB, MGD-014 and VRC07.

Pharmacokinetic Enhancers

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

Additional Therapeutic Agents

Examples of additional therapeutic agents include the compoundsdisclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (GileadSciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (GileadSciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (GileadSciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (GileadSciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (Universityof Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380(Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034(Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO2013/091096 (Boehringer Ingelheim).

HIV Vaccines

Examples of HIV vaccines include peptide vaccines, recombinant subunitprotein vaccines, live vector vaccines, DNA vaccines, CD4-derivedpeptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV(vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype Cvaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401),Vacc-4x, Vacc-05, VAC-3S, multiclade DNA recombinant adenovirus-5(rAdS), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax,Ad35, Ad35-GRIN, NAcGM3NSSP ISA-51, poly-ICLC adjuvanted vaccines,Tatlmmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4,HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123,rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env CladeC+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101,CombiHlVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env,Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001,ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particlevaccines such as pseudovirion vaccine, CombiVlCHvac, LFn-p24 B/C fusionvaccine, GTU-based DNA vaccine, HIV gag/pol/nef/env DNA vaccine,anti-TAT HIV vaccine, conjugate polypeptides vaccine, dendritic-cellvaccines, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIVvaccine (PIKA adjuvant), I i-key/MHC class II epitope hybrid peptidevaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVAvaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine,recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine,RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIVvaccine, UBI HIV gp120, Vacc-4x+romidepsin, variant gp120 polypeptidevaccine, rAd5 gag-pol env A/B/C vaccine.

HIV Combination Therapy

In a particular embodiment, a pharmaceutically acceptable salt ofCompound 1, or crystalline form thereof, disclosed herein is combinedwith one, two, three, four or more additional therapeutic agentsselected from ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, andemtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxilfumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat,tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovirdisoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofoviralafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide,emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide,emtricitabine, cobicistat, and elvitegravir); adefovir; adefovirdipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil;tenofovir disoproxil fumarate; tenofovir alafenamide; tenofoviralafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir, andlamivudine); dolutegravir, abacavir sulfate, and lamivudine;raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA®(KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine andlamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate andlamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate, zidovudine, andlamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride;atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavirand cobicistat; atazanavir; atazanavir sulfate; dolutegravir;elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir;lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz;etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine;stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine;zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin;zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate;Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate;efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid;lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or crystalline form thereof, disclosed herein is combined with one, two,three, four or more additional therapeutic agents selected from ATRIPLA®(efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA®(EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, andemtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovirdisoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxilfumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamideand emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, andrilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine,cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat;emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxilfumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate;TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir,abacavir sulfate, and lamivudine; raltegravir; raltegravir andlamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir andritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM®(LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavirsulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine;rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavirand cobicistat; darunavir and cobicistat; atazanavir; atazanavirsulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate andritonavir; darunavir; lamivudine; prolastin; fosamprenavir;fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavirmesylate; interferon; didanosine; stavudine; indinavir; indinavirsulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir;saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir;delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine andtenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovirdisoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine;abacavir; abacavir sulfate; 4′-ethynyl-2-fluoro-2′-deoxyadenosine(EFdA); and Bictegravir, or a pharmaceutically acceptable salt thereof.

It will be appreciated by one of skill in the art that the additionaltherapeutic agents listed above may be included in more than one of theclasses listed above. The particular classes are not intended to limitthe functionality of those compounds listed in those classes.

In a specific embodiment a pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, disclosed herein iscombined with one or two HIV nucleoside or nucleotide inhibitors ofreverse transcriptase. In a specific embodiment, a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, disclosed herein is combined with an HIV nucleoside ornucleotide inhibitor of reverse transcriptase and an HIV non-nucleosideinhibitor of reverse transcriptase. In another specific embodiment, apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase, and an HIVprotease inhibiting compound. In an additional embodiment, apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase, an HIVnon-nucleoside inhibitor of reverse transcriptase, and a pharmacokineticenhancer. In certain embodiments, a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, disclosed hereinis combined with at least one HIV nucleoside inhibitor of reversetranscriptase, an integrase inhibitor, and a pharmacokinetic enhancer.In another embodiment, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein is combinedwith two HIV nucleoside or nucleotide inhibitors of reversetranscriptase.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein is combinedwith one or two HIV nucleoside or nucleotide inhibitors of reversetranscriptase. In a specific embodiment, a pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof,disclosed herein is combined with an HIV nucleoside or nucleotideinhibitor of reverse transcriptase and an HIV non-nucleoside inhibitorof reverse transcriptase. In another specific embodiment, apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase, and an HIVprotease inhibiting compound. In an additional embodiment, apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein is combined with an HIVnucleoside or nucleotide inhibitor of reverse transcriptase, an HIVnon-nucleoside inhibitor of reverse transcriptase, and a pharmacokineticenhancer. In certain embodiments, a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, disclosed hereinis combined with at least one HIV nucleoside inhibitor of reversetranscriptase, an integrase inhibitor, and a pharmacokinetic enhancer.In another embodiment, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein is combinedwith two HIV nucleoside or nucleotide inhibitors of reversetranscriptase.

In a particular embodiment, a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, disclosed hereinis combined with abacavir sulfate, tenofovir, tenofovir disoproxil,tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate,tenofovir alafenamide, tenofovir alafenamide fumarate or tenofoviralafenamide hemifumarate.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein is combinedwith abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovirdisoproxil fumarate, tenofovir disoproxil hemifumarate, tenofoviralafenamide, tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, bictegravir (or a pharmaceutically acceptable saltthereof), or 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA).

In a particular embodiment, a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, disclosed hereinis combined with tenofovir, tenofovir disoproxil, tenofovir disoproxilfumarate, tenofovir alafenamide, tenofovir alafenamide fumarate ortenofovir alafenamide hemifumarate.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein is combinedwith tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir alafenamide, tenofovir alafenamide fumarate, tenofoviralafenamide hemifumarate, bictegravir (or a pharmaceutically acceptablesalt thereof), or 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA).

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein apharmaceutically acceptable salt of Compound 1, or crystalline formthereof, disclosed herein is combined with a first additionaltherapeutic agent selected from the group consisting of abacavirsulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate,tenofovir alafenamide, tenofovir alafenamide fumarate and tenofoviralafenamide hemifumarate, and a second additional therapeutic agentselected from the group consisting of emtricitabine and lamivudine.

In a particular embodiment, a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, disclosed hereinis combined with a first additional therapeutic agent selected from thegroup consisting of tenofovir, tenofovir disoproxil, tenofovirdisoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamidehemifumarate, and a second additional therapeutic agent, wherein thesecond additional therapeutic agent is emtricitabine. In a particularembodiment, a pharmaceutically acceptable salt of Compound 1, or acocrystal or crystalline form thereof, disclosed herein is combined witha first additional therapeutic agent selected from the group consistingof tenofovir alafenamide fumarate, tenofovir alafenamide, and tenofoviralafenamide hemifumarate, and a second additional therapeutic agent,wherein the second additional therapeutic agent is emtricitabine. In aparticular embodiment, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein is combinedwith a first additional therapeutic agent selected from the groupconsisting of tenofovir disoproxil fumarate, tenofovir disoproxil, andtenofovir disoproxil hemifumarate, and a second additional therapeuticagent, wherein the second additional therapeutic agent is emtricitabine.In some embodiments, the pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, and the first and secondadditional therapeutic agents as disclosed above are administeredsimultaneously. Optionally, the pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, and the firstand second additional therapeutic agents as disclosed above are combinedin a unitary dosage form for simultaneous administration to a subject.In other embodiments, the pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, and the first and secondadditional therapeutic agents as disclosed above are administeredsequentially.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein is combinedwith bictegravir or a pharmaceutically acceptable salt thereof.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein is combinedwith 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA).

A pharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein may be combined with one ormore additional therapeutic agents in any dosage amount of thepharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof (e.g., from 1 mg to 1000 mg of the salt orcrystalline form).

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein may becombined with one or more additional therapeutic agents in any dosageamount of the pharmaceutically acceptable salt of Compound 1, or acocrystal or crystalline form thereof (e.g., from 1 mg to 1000 mg of thesalt, cocrystal, or crystalline form).

In certain embodiments, a pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, disclosed herein iscombined with 5-30 mg tenofovir alafenamide fumarate, tenofoviralafenamide hemifumarate, or tenofovir alafenamide, and 200 mgemtricitabine. In certain embodiments, a pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof,disclosed herein is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30,15-30, or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Incertain embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein is combinedwith 10 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Incertain embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein is combinedwith 25 mg tenofovir alafenamide fumarate, tenofovir alafenamidehemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. Apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein may be combined with theagents provided herein in any dosage amount of the salt, cocrystal, orcrystalline form (e.g., from 1 mg to 1000 mg of the salt, cocrystal, orcrystalline form) the same as if each combination of dosages werespecifically and individually listed.

In certain embodiments, a pharmaceutically acceptable salt of Compound1, or a cocrystal or crystalline form thereof, disclosed herein, iscombined with 200-400 mg tenofovir disoproxil fumarate, tenofovirdisoproxil hemifumarate, or tenofovir disoproxil, and 200 mgemtricitabine. In certain embodiments, a pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof,disclosed herein is combined with 200-250, 200-300, 200-350, 250-350,250-400, 350-400, 300-400, or 250-400 mg tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mgemtricitabine. In certain embodiments, a pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof,disclosed herein is combined with 300 mg tenofovir disoproxil fumarate,tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mgemtricitabine. A pharmaceutically acceptable salt of Compound 1, or acocrystal or crystalline form thereof, disclosed herein may be combinedwith the agents provided herein in any dosage amount of the salt,cocrystal, or crystalline form (e.g., from 1 mg to 1000 mg of the salt,cocrystal, or crystalline form) the same as if each combination ofdosages were specifically and individually listed.

In some embodiments, a pharmaceutically acceptable salt of Compound 1,or a cocrystal or crystalline form thereof, disclosed herein is combinedwith 20-80 mg of bictegravir or a pharmaceutically acceptable saltthereof. A pharmaceutically acceptable salt of Compound 1, or acocrystal or crystalline form thereof, disclosed herein may be combinedwith the agents provided herein in any dosage amount of the salt,cocrystal, or crystalline form (e.g., from 1 mg to 1000 mg of the salt,cocrystal, or crystalline form) the same as if each combination ofdosages were specifically and individually listed.

In one embodiment, kits comprising a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, disclosed hereinin combination with one or more (e.g., one, two, three, one or two, orone to three) additional therapeutic agents are provided.

In some embodiments, kits comprising a pharmaceutically acceptable saltof Compound 1, or a cocrystal or crystalline form thereof, disclosedherein in combination with one or more (e.g., one, two, three, one ortwo, or one to three) additional therapeutic agents are provided.

Pharmaceutical Compositions

Pharmaceutical compositions disclosed herein comprise a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, disclosed herein together with one or more pharmaceuticallyacceptable excipients and optionally other therapeutic agents.Pharmaceutical compositions containing the active ingredient may be inany form suitable for the intended method of administration.

In some embodiments, pharmaceutical compositions disclosed hereincomprise a pharmaceutically acceptable salt of Compound 1, or acocrystal or crystalline form thereof, disclosed herein together withone or more pharmaceutically acceptable excipients and optionally othertherapeutic agents. Pharmaceutical compositions containing the activeingredient may be in any form suitable for the intended method ofadministration.

Pharmaceutical compositions comprising the pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof,disclosed herein may be prepared with conventional carriers (e.g.,inactive ingredient or excipient material) which may be selected inaccord with ordinary practice. Tablets may contain excipients includingglidants, fillers, binders and the like. Aqueous compositions may beprepared in sterile form, and when intended for delivery by other thanoral administration generally may be isotonic. All compositions mayoptionally contain excipients such as those set forth in the Rowe et al,Handbook of Pharmaceutical Excipients, 5th edition, American PharmacistsAssociation, 1986. Excipients can include ascorbic acid and otherantioxidants, chelating agents such as EDTA, carbohydrates such asdextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearicacid and the like.

While it is possible for the active ingredient to be administered alone,it may be preferable to present the active ingredient as pharmaceuticalcompositions. The compositions, both for veterinary and for human use,comprise at least the pharmaceutically acceptable salt of Compound 1, ora cocrystal or crystalline form thereof, disclosed herein together withone or more acceptable carriers and optionally other therapeuticingredients. In one embodiment, the pharmaceutical composition comprisesa pharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, a pharmaceutically acceptable excipient, and atherapeutically effective amount of one or more (e.g., one, two, three,or four; or one or two; or one to three; or one to four) additionaltherapeutic agents as defined hereinbefore. In one embodiment, thepharmaceutical composition comprises a pharmaceutically acceptable saltof Compound 1, or a cocrystal or crystalline form thereof, apharmaceutically acceptable excipient, and one other therapeuticingredient. The carrier(s) are “acceptable” in the sense of beingcompatible with the other ingredients of the composition andphysiologically innocuous to the recipient thereof.

The compositions include those suitable for various administrationroutes. The compositions may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Such methods include the step of bringing into association theactive ingredient with one or more inactive ingredients (e.g., acarrier, pharmaceutical excipient, etc.). The compositions may beprepared by uniformly and intimately bringing into association theactive ingredient with liquid carriers or finely divided solid carriersor both, and then, if necessary, shaping the product. Techniques andformulations generally are found in Remington: The Science and Practiceof Pharmacy, 21^(st) Edition, Lippincott Wiliams and Wilkins,Philadelphia, Pa., 2006.

Compositions described herein that are suitable for oral administrationmay be presented as discrete units (a unit dosage form) including butnot limited to capsules, cachets or tablets each containing apredetermined amount of the active ingredient.

When used for oral use for example, tablets, troches, lozenges, aqueousor oil suspensions, dispersible powders or granules, emulsions, hard orsoft capsules, syrups or elixirs may be prepared. Compositions intendedfor oral use may be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions and such compositionsmay contain one or more agents including sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apalatable preparation. Tablets containing the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipient which aresuitable for manufacture of tablets are acceptable. These excipients maybe, for example, inert diluents, such as calcium or sodium carbonate,lactose, lactose monohydrate, croscarmellose sodium, povidone, calciumor sodium phosphate; granulating and disintegrating agents, such asmaize starch, or alginic acid; binding agents, such as cellulose,microcrystalline cellulose, starch, gelatin or acacia; and lubricatingagents, such as magnesium stearate, stearic acid or talc. Tablets may beuncoated or may be coated by known techniques includingmicroencapsulation to delay disintegration and adsorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

In some embodiments, disclosed herein are oral dosage forms (e.g.,tablets), which may be prepared from hot melt extrusion or spray-dryingdispersion (SDD) technologies.

In some embodiments, disclosed herein are hard capsules filled withpowder, beads, or granules containing the active ingredient in admixturewith non-toxic pharmaceutically acceptable excipient which are suitablefor manufacture of hard or soft capsules. These excipients may be, forexample, inert diluents, such as calcium or sodium carbonate, lactose,lactose monohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc.

In some embodiments, disclosed herein are hard or soft capsules filledwith liquid or semi-solid mixtures containing the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipient which aresuitable for manufacture of hard or soft capsules. These excipients maybe, for example, solubilizing oils such as maize oil, sesame oil, orcorn oil; medium chain triglycerides and related esters, such as,derivitized palm kernel oil or coconut oil; self-emulsifying lipidsystems (SEDDS or SMEDDS), such as caprylic triglyceride or propyleneglycol monocaprylate; viscosity modifiers, such as, cetyl alcohol,steryl alcohol, glycerol stearate; and solubilizing agents andsurfactants, such as polyethylene glycol, propylene glycol, glycerin,ethanol, polyethoxylated castor oil, poloxamers, or polysorbates.

The pharmaceutical compositions of the present disclosure may be in theform of a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned herein. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

In some embodiments, the sterile injectable preparation disclosed hereinmay also be a sterile injectable solution or suspension prepared from areconstituted lyophilized powder in a non-toxic parenterally acceptablediluent or solvent, such as a solution in 1,3-butane-diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile fixed oils may conventionally be employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid may likewise be used in the preparation of injectables.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. In certain embodiments the suspension is a microsuspension. Incertain embodiments the suspension is a nanosuspension.

In some embodiments, formulations suitable for parenteral administration(e.g., intramuscular (IM) and subcutaneous (SC) administration) willinclude one or more excipients. Excipients should be compatible with theother ingredients of the formulation and physiologically innocuous tothe recipient thereof. Examples of suitable excipients are well known tothe person skilled in the art of parenteral formulation and may be founde.g., in Handbook of Pharmaceutical Excipients (eds. Rowe, Sheskey &Quinn), 6th edition 2009.

Examples of solubilizing excipients in a parenteral formulation (e.g.,an SC or IM formulation) include, but are not limited to, polysorbates(such as polysorbate 20 or 80) and poloxamers (such as poloxamer 338,188, or 207). In some embodiments, disclosed herein is a parenteraladministration (e.g., an SC or IM formulation) that comprises apharmaceutically acceptable salt of Compound 1, or crystalline formthereof, disclosed herein and a poloxamer, in particular poloxamer 338.In some embodiments, the amount of poloxamer (e.g., poloxamer 388) in aparenteral administration disclosed herein is less than about 5%, suchas less than about 3%, about 2%, about 1%, or about 0.5%.

In some embodiments, the parenteral formulation (e.g., an SC or IMformulation) disclosed herein is an aqueous suspension. In someembodiments, the parenteral formulation (e.g., an SC or IM formulation)disclosed herein is an aqueous suspension that comprises apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein and saline. In someembodiments, the parenteral formulation (e.g., an SC or IM formulation)disclosed herein is an aqueous suspension that comprises apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein saline, and a poloxamer (suchas poloxamer 338, 188, or 207).

In certain embodiments, the composition is disclosed as a solid dosageform, including a solid injectable dosage form, such as a solid depotform.

The amount of active ingredient that may be combined with the inactiveingredients to produce a dosage form may vary depending upon theintended treatment subject and the particular mode of administration.For example, in some embodiments, a dosage form for oral administrationto humans may contain approximately 1 to 1000 mg of active materialformulated with an appropriate and convenient amount of carrier material(e.g., inactive ingredient or excipient material). In certainembodiments, the carrier material varies from about 5 to about 95% ofthe total compositions (weight:weight).

It should be understood that in addition to the ingredients particularlymentioned above the compositions of these embodiments may include otheragents conventional in the art having regard to the type of compositionin question, for example those suitable for oral administration mayinclude flavoring agents.

In certain embodiments, a composition comprising an active ingredientdisclosed herein in one variation does not contain an agent that affectsthe rate at which the active ingredient is metabolized. Thus, it isunderstood that compositions comprising a pharmaceutically acceptablesalt of Compound 1, or a cocrystal or crystalline form thereof, incertain embodiments do not comprise an agent that would affect (e.g.,slow, hinder or retard) the metabolism of the pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, or any other active ingredient administered separately,sequentially or simultaneously with the salt, cocrystal, or crystallineform. It is also understood that any of the methods, kits, articles ofmanufacture and the like detailed herein in certain embodiments do notcomprise an agent that would affect (e.g., slow, hinder or retard) themetabolism of a pharmaceutically acceptable salt of Compound 1, or acocrystal or crystalline form thereof, or any other active ingredientadministered separately, sequentially or simultaneously with thepharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof.

Kits and Articles of Manufacture

The present disclosure relates to a kit comprising a pharmaceuticallyacceptable salt of Compound 1, or a cocrystal or crystalline formthereof, disclosed herein. In one embodiment, the kit may comprise oneor more additional therapeutic agents as described hereinbefore. The kitmay further comprise instructions for use, e.g., for use in inhibitingan HIV reverse transcriptase, such as for use in treating an HIVinfection or AIDS or as a research tool. The instructions for use aregenerally written instructions, although electronic storage media (e.g.,magnetic diskette or optical disk) containing instructions are alsoacceptable.

The present disclosure also relates to a pharmaceutical kit comprisingone or more containers comprising a pharmaceutically acceptable salt ofCompound 1, or a cocrystal or crystalline form thereof, disclosedherein. Optionally associated with such container(s) can be a notice inthe form prescribed by a governmental agency regulating the manufacture,use or sale of pharmaceuticals, which notice reflects approval by theagency for the manufacture, use or sale for human administration. Eachcomponent (if there is more than one component) can be packaged inseparate containers or some components can be combined in one containerwhere cross-reactivity and shelf life permit. The kits may be in unitdosage forms, bulk packages (e.g., multi-dose packages) or sub-unitdoses. Kits may also include multiple unit doses of the compounds andinstructions for use and be packaged in quantities sufficient forstorage and use in pharmacies (e.g., hospital pharmacies and compoundingpharmacies).

In some embodiments, the present disclosure also relates to apharmaceutical kit comprising one or more containers comprising apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein. Optionally associated withsuch container(s) can be a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals, which notice reflects approval by the agency for themanufacture, use or sale for human administration. Each component (ifthere is more than one component) can be packaged in separate containersor some components can be combined in one container wherecross-reactivity and shelf life permit. The kits may be in unit dosageforms, bulk packages (e.g., multi-dose packages) or sub-unit doses. Kitsmay also include multiple unit doses of the compounds and instructionsfor use and be packaged in quantities sufficient for storage and use inpharmacies (e.g., hospital pharmacies and compounding pharmacies).

Also disclosed are articles of manufacture comprising a unit dosage of apharmaceutically acceptable salt of Compound 1, or a cocrystal orcrystalline form thereof, disclosed herein in suitable packaging for usein the methods described herein. Suitable packaging is known in the artand includes, for example, vials, vessels, ampules, bottles, jars,flexible packaging and the like. An article of manufacture may furtherbe sterilized and/or sealed.

EXAMPLES General Methods X-Ray Powder Diffraction (XRPD)

XRPD patterns were collected on a PANanalytical XPERT-PRO diffractometerat ambient conditions under the following experimental settings: 45 KV,40 mA, Kα1=1.5406 Å, scan range 2 to 40°, step size 0.0084 or 0.0167°,measurement time: 5 min.

Differential Scanning Calorimetry (DSC)

DSC thermograms were collected on a TA Instruments Q2000 system equippedwith a 50 position auto-sampler. The calibration for energy andtemperature was carried out using certified indium. Typically 1-5 mg ofeach sample, in a pin-holed aluminium pan, was heated at 10° C./min from25° C. to 300° C. A purge of dry nitrogen at 50 mL/min was maintainedover the sample throughout the measurement. The onset of the meltingendotherm was reported as the melting point.

Proton Nuclear Magnetic Resonance (¹H NMR)

¹H NMR spectra were collected on a Varian 400-MR 400MHz instrument with7620AS sample changer. The default proton parameters are as follows:spectral width: 14 to −2 ppm (6397.4 Hz); relaxation delay: 1 sec;pulse: 45 degrees; acquisition time: 2.049 sec; number of scans orrepetitions: 8; temperature: 25° C. Samples were prepared in dimethylsulfoxide-d_(6,) unless otherwise stated. Off-line analysis was carriedout using MestReNova software.

Intermediate 1. tert-Butyl(S)-(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluoropphenyl)ethyl)carbamate

Step 1.(S)—N—((3,6-Dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide

3,6-Dibromopicolinaldehyde (76.0 g, 0.287 mol) and(S)-2-methylpropane-2-sulfinamide (36.51g, 0.301 mol) were combined inNMP (N-methyl-2-pyrrolidone) (200 mL). To the reaction mixture was addedCs₂CO₃ (41.94 g, 0.316 mol). The reaction mixture was stirred for about2 h and then cooled to about 5° C. Water (1.3 L) was added to thereaction mixture. The resulting suspension was stirred for about 1 h,solids isolated by filtration, washed with water (5×100 mL) and dried toprovide the title compound. MS (m/z) 368.9 [M+H]+.

Step 2.(S)—N—((S)-1-(3,6-Dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide

A reaction vessel was charged with(S)—N—((3,6-dibromopyridin-2-yl)methylene)-2-methylpropane-2-sulfinamide(65.5 g, 177.95 mmol) followed by DMF (dimethylformamide) (260 mL). Themixture was stirred for about 5 min until homogeneous and the solutionwas cooled to about 8° C. To the reaction mixture was added(3,5-difluorobenzyl)zinc bromide (0.5 M in tetrahydrofuran (THF), 516.04mL) dropwise over about 90 mins. The mixture was stirred for about anadditional 2.5 h. To the reaction mixture, 5% AcOH (acetic acid) inwater (640 mL) was added over about 10 mins followed by CPME(cyclopentyl methyl ether) (320 mL) in one portion. The mixture wasstirred for about 5 mins, warmed to room temperature, and the layerswere separated. The organic layer was washed with 5% AcOH (320 mL) thentreated with 0.5M NaOH (330 mL) and washed with brine. The organic layerwas collected, dried with Na2SO4, and filtered. To the crude mixture wasadded MeOH (methanol) (33 mL). To the stirring mixture was addeddropwise 3M HCl in CPME (128 mL) over about 15 mins. After stirring forabout 1 h, the precipitate was removed by filtration. The filtrate wasdiluted with hexane (300 mL) and the product was extracted with water(450 mL). The aqueous layer was basified with 8M NaOH and extracted withCPME (375 mL). The organic layer was washed with brine, dried overNa₂SO₄ and filtered to provide the title compound in solution which wasused directly in the next reaction. MS (m/z) 497.0 [M+H]+.

Step 3.(S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5difluorophenyl)ethan-1-amine

The resulting solution of(S)—N—((S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenypethyl)-2-methylpropane-2-sulfinamidewas diluted with CPME to a volume of 700 mL to which acetonitrile (350mL) was added. To the stirring mixture, concentrated HCl (37%, 16.4 mL)was added dropwise over about 10 mins at room temperature. The thickslurry was vigorously stirred for about 4 h. The solids were filteredand washed with 2:1 CPME (cyclopropyl methyl ether):ACN to provide thetitle compound. MS (m/z) 393.3 [M+H]+.

Step 4. tert-Butyl(S)-(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate

A reaction vessel was charged with 2-MeTHF (190 mL), water (190 mL) and(S)-1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethan-1-amine(46.9 g, 0.11 mol) followed by portionwise addition of NaHCO₃ (30.34 g,0.36 mol). The reaction mixture was cooled to about 5° C. anddi-tert-butyl dicarbonate (27.47 g, 0.13 mol) was added. The reactionmixture was stirred at about 0° C. for about 2 h and ambient temperaturefor about 2 h. The reaction mixture was diluted with water and extractedwith MTBE (methyl tert-butyl ether). The organic layers were washed withbrine, dried and concentrated. Crude compound was purified by columnchromatography on silica to provide the title compound. MS (m/z) 492.8[M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 7.85 (d, 1H), 7.42 (d, 1H),6.90-6.72 (m, 3H), 5.33 (dd, 1H), 3.10 (dd, 1H), 2.92 (dd, 1H), 1.36 (s,9H).

Intermediate 2.4-Chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine

Step 1. 7-Bromo-4-chloro-1H-indazol-3-amine

To 3-bromo-6-chloro-2-fluorobenzonitrile (13.9 g, 59.3 mmol) in EtOH(ethanol) (60 mL) was added hydrazine monohydrate (5.77 mL). Thereaction mixture was heated to about 80° C. for about 3 h. After coolingto ambient temperature, EtOH (20 mL) was added to allow for stirring.The solids were isolated by filtration, washed with cold EtOH, and driedto provide the title compound. MS (m/z) 247.9 [M+H]⁺.

Step 2. 7-Bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine

A reactor was charged with 7-bromo-4-chloro-1H-indazol-3-amine (397.2 g,1.6 mol) and Cs₂CO₃ (1052 g, 3.2 mol) then diluted with DMF(dimethylformamide) (4000 mL). To this was slowly added2,2,2-trifluoroethyl trifluoromethanesulfonate (463.2 g, 1.9 mol) viaaddition funnel. Upon completion of the addition, the reaction mixturewas allowed to stir for about 1 hour, at which time, H₂O (16 L) wasadded slowly. Upon completion of the addition, the mixture was allowedto stir for about 12 hours at about 15° C. The slurry was filtered andthe collected solids were suspended in DMF (800 mL). To this was addedH₂O (4800 mL) and the resulting solids were collected by filtration anddried to provide the title compound. MS (m/z) 330.1 [M+H]⁺.

Step 3. 4-Chloro-7-(4, 4, 5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine

A reaction vessel was charged with7-bromo-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine (15.00 g,45.66 mmol), bis(pinacolato)diboron (17.39 g, 68.49 mmol), potassiumpropionate (15.36 g, 136.98 mmol), dioxane (90 mL) and DMF(dimethylformamide) (30 mL). Bis(triphenylphosphine)palladium(II)dichloride (0.64g, 0.91 mmol) was added and the reaction solutiondegassed by bubbling argon for about 2 min. The reaction mixture washeated to about 105° C. for about 4 hrs. After cooling to ambienttemperature, the reaction mixture was filtered through a pad of Celiteand silica gel washing with EtOAc. The filtrate was washed with 5% LiC1solution and brine. The organic layers were separated, dried, andconcentrated under reduced pressure. The residue was treated withIPAc/heptane (1/10) at about 60° C. then cooled to ambient temperatureand stirred for about 15 h. The solids were collected by filtration anddried to afford the title compound. MS (m/z) 376.7 [M+H]⁺ ¹H NMR (400MHz, DMSO-d₆) δ 7.69 (d, 1H), 7.06 (d, 1H), 5.55 (s, 2H), 5.45 (q, 2H),1.32 (s, 12H).

Intermediate 3.2-((3bS,4aR)-5,5-Difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid

Step 1. Lithium2,2,2-trifluoro-1-(3-oxobicyclo[3.1.0]hexan-2-ylidene)ethan-1-olate

A reactor was charged with bicyclo[3.1.0]hexan-3-one (95.6 g, 0.99 mol)and ethyl 2,2,2-trifluoroacetate (113.2 mL, 0.95 mol) and THF (50 mL).The reaction mixture was cooled to about 0° C. LiHMDS (Lithiumbis(trimethylsilyl)amide) (1L of 1.0M solution in THF, 1 mol) was addedvia an addition funnel at a rate to maintain internal temperature belowabout 1° C. After the addition was complete, hexanes (235 mL) was addedin a steady stream via an addition funnel and stirred for about 15 min.The resultant solids were collected by filtration, washed with hexanes(3×400 mL), and dried to provide the title compound.

Step 2. Ethyl2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate

A reactor was charged with lithium2,2,2-trifluoro-1-(3-oxobicyclo[3.1.0]hexan-2-ylidene)ethan-1-olate(177.2 g, 0.89 mol) and EtOH (ethanol) (779 mL). The temperature wasbrought to and maintained at about 0° C. HCl in dioxane (4.0 N, 443 mL)was added via an addition funnel followed by the addition of solid ethylhydrazinoacetate HCl salt (138.4 g, 0.90 mol). The reaction temperaturewas adjusted to about 35° C. After about 1 h, the reaction volume wasreduced by ˜40% by distillation at reduced pressure. Water (1.3 L) wasadded with vigorous agitation and temperature adjusted to about 15° C.The resultant solids were collected by filtration, washed with water(3×500 mL), hexanes (3×400 mL), and dried to provide the title compound.MS (m/z) 275.1 [M+H]⁺.

Step 3. Ethyl2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate

A reactor was charged with ethyl2-(3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(291.2 g, 1.06 mol), I (acetonitrile) (1.65 L) and water (825 mL) towhich N-hydroxyphthalimide (17.4 g, 0.103 mol) and NaClO₂ (41.0 g, 0.45mol, ˜20% of total amount to be added) were added. The reaction mixturewas heated to about 50° C. and the remaining NaClO₂ (163.0 g, 1.80 mol)was added in five portions over about 2 h. After consumption of startingmaterial, the temperature was adjusted to about 20° C. and aqueoussodium bisulfite (40% w/w, 350 mL) was added via an addition funnel.Ethyl acetate (1.75 L) was added and the layers were separated. Theaqueous layer was back extracted with EtOAc (ethyl acetate) (500 mL).The organic layers were combined and washed with saturated aqueousNaHCO₃ (500 mL) and 1:1 water/ brine (500 mL). The organic layer wasconcentrated under reduced pressure and co-evaporated with IPAc(isopropyl acetate) (300 mL). The crude solid was crystallized from amixture of IPAc /heptane. The resultant solids were collected byfiltration, washed with heptane, and dried to provide the titlecompound. MS (m/z) 289.0 [M+H]⁺.

Step 4.2-(5-Oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid

To a solution of ethyl2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetate(80.40 g, 278.95 mmol) in 2-MeTHF (2-methyltetrahydrofuran) (167 mL) wasadded 2M aqueous sodium hydroxide (167 mL). After about 25 minutes ofstirring at room temperature, the reaction mixture was diluted with2-MeTHF and was slowly acidified by the dropwise addition ofconcentrated HCl. The organic layer was isolated and the aqueous layerwas extracted with an additional portion of 2-MeTHF. The combinedorganic layers were washed with saturated aqueous sodium chloride, thendried over sodium sulfate, filtered, and concentrated. The resulting oilwas taken in ethyl acetate. Hexanes was added with vigorous stirringuntil solid formation was observed. The solid was isolated by filtrationand dried to provide the title compound. MS (m/z) 259.00 [M−H]⁻.

Step 5.2-(3-(Trifluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2′-[1,3]dithiolane]-1(3bH)-yl)aceticacid

To a solution of2-(5-oxo-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (3.0 g, 11.5 mmol) in DCM (dichloromethane) (25 mL) was added1,2-ethanedithiol (1.07 mL, 12.68 mmol) followed by borontrifluoride-acetic acid complex (4.0 mL, 28.8 mmol). The reactionmixture was stirred at room temperature overnight. To the reactionmixture was added water (60 mL) and 2-MeTHF (60 mL). The organic layerwas isolated, dried over sodium sulfate, filtered, and concentrated. Thecrude was dissolved in ethyl acetate (2 mL) and the solution dilutedwith hexanes (12 mL) with vigorous stirring to provide a solid. Thesolid was isolated by filtration and dried to provide the titlecompound. MS (m/z) 337.12 [M+H]⁺.

Step 6.2-(5,5-Difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid

To a suspension of 1,3-dibromo-5,5-dimethylhydantoin (12.75 g, 44.6mmol) in DCM (35 mL) was added pyridine hydrofluoride (5.0 mL) at about0° C. The suspension was stirred at about 0° C. for about 10 minutes. Tothe suspension was added a solution of2-(3-(trifluoromethyl)-4,4a-dihydrospiro[cyclopropa[3,4]cyclopenta[1,2-c]pyrazole-5,2′-[1,3]dithiolane]-1(3bH)-yl)aceticacid (5.00 g, 14.9 mmol) dropwise. After addition was complete, thereaction mixture was stirred at about 0° C. for about an additional 15minutes. The reaction mixture was poured into saturated aqueous sodiumbicarbonate solution (300 mL) with vigorous stirring. The organic layerwas removed and the aqueous layer was acidified to pH ˜1 withconcentrated HCl. The aqueous phase was extracted with three portions ofMTBE (methyl tent-butyl ether). The combined organic layers were driedover sodium sulfate, filtered, and concentrated. The resulting solid wastaken in MTBE (16 mL) and filtered to remove any resulting solid. Thesolution was then extracted with 2N NaOH (16 mL). The aqueous layer wasdiluted with water (16 mL) with vigorous stirred and stirred at roomtemperature for about 15 minutes. The resulting solid was removed byfiltration. The aqueous layer was acidified by slow, dropwise additionof concentrated HCl to pH ˜1 with vigorous stirring to provide a solidprecipitate. The solid was isolated by filtration to provide the titlecompound. MS (m/z) 281.12 [M+H]⁺.

Step 7.2-((3bS,4aR)-5,5-Difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid

2-(5,5-Difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid was separated to its constituent enantiomers(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (Intermediate 3) and2-((3bR,4aS)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid), by chiral supercritical fluid chromatography (SFC) under thefollowing conditions: Instrument: Thar 350 preparative SFC; Column:ChiralPak IC-10 u, 300×50mmI.D; Mobile phase: 35% Isopropanol (0.1%NH_(3.)H₂O) and CO₂; Flow rate: 200 mL/min; Column temperature: 38° C.;UV detection: 220 nm; Sample preparation: Compound was dissolved inisopropanol to ˜45 mg/mL; Injection: 6.5 mL per injection. AnalyticalSFC [mobile phase: A for CO₂ and B for Isopropanol (0.05% DEA);Gradient: B 20%; A; Flow rate: 2.35 mL/min; Column: Chiralpak IC-3,150×4.6 mm, 3 μm; Wavelength: 254 nm]. The desired isomer,2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid, eluted at t =3.39 min; ¹H NMR (400 MHz, Chloroform-d) δ 4.93 (s,2H), 2.52-2.43 (m, 2H), 1.44-1.38 (m, 1H), 1.15 (m, 1H).

Intermediate 4: 3-methyl-3-(methylsulfonyl)but-1-yne:

To a stirred suspension of sodium methanesulfinate (18.47 g, 175.5 mmol)and copper(I) chloride (1.45 g, 14.6 mmol) in DMF (dimethylformamide)(50 mL) was added 3-chloro-3-methylbut-1-yne (15.00 g, 146.3 mmol, 16.4mL) dropwise. The resulting reaction mixture was heated to about 40° C.and stirred for about 16 h. The reaction mixture was cooled to roomtemperature and diluted with EtOAc. The solution was washed with waterand brine. The organic layer was collected and dried over sodiumsulfate, then filtered. The solution was concentrated under vacuum andpurified by silica gel chromatography to provide the title compound. Mp:115-116° C. ¹H NMR (400 MHz, Chloroform-d) δ 3.04 (s, 3H), 2.58 (s, 1H),1.67 (s, 6H).

Example 1N—((S)-1-(3-(4-Chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenypethyl)-2-43bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide(Compound 1)

Step 1. tert-Butyl(S)-(1-(3-bromo-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5difluorophenyl)ethyl)carbamate

A reactor was charged with tent-butyl(S)-(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(Intermediate 1, 50.00 g, 101.8 mmol),3-methyl-3-methylsulfonyl-but-1-yne (17.86 g, 122.2 mmol), DMF(dimethylformamide) (90 mL) and Et₃N (trimethylamine) (42.5 mL, 305.4mmol). The reaction mixture was heated to about 50° C.Bis(triphenylphosphine)palladium(II) dichloride (2.14 g, 3.1 mmol) andcopper(I) iodide (0.58 g, 3.1 mmol) were added. After about 30 min, thereaction mixture was diluted with MeCN (acetonitrile) (200 mL) and then7% aq. NH₄Cl (200 mL) was added dropwise. A slurry was formed andadjusted to ambient temperature. After about 3 h, the solids werecollected by filtration. The cake was washed with MeCN/water (1:1, 75mL) twice and MTBE (methyl tent-butyl ether) (75 mL). The solid wasdried to provide the title compound. MS (m/z) 556 [M+H]⁺. ¹H NMR (400MHz, Chloroform-d) δ 7.84 (d, J=8.2 Hz, 1H), 7.29-7.15 (m, 1H),6.70-6.55 (m, 2H), 5.79 (d, J=9.0 Hz, 1H), 5.57-5.45 (m, 1H), 3.21-3.05(m, 4H), 2.99-2.88 (m, 1H), 1.80 (s, 6H), 1.40* (s, 7H), 1.30* (s, 2H).*denotes presence of atropisomers in 4.6:1 ratio.

Step 2. tert-Butyl(S)-(1-(3-(3-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate

tert-Butyl(S)-(1-(3-bromo-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(1000.0 mg, 1.79 mmol),4-chloro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-amine(808.5 mg, 2.15 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (65.6 mg,0.09 mmol), and cesium carbonate (876.7 mg, 2.69 mmol) were charged in around bottom flask and placed under argon. Dioxane (10 mL) and water (2mL) were added, and the suspension was degassed by bubbling argon forabout 1 minute. After degassing, the reaction flask was fitted with areflux condenser and heated to about 80° C. for overnight. The reactionmixture was cooled to room temperature, and the aqueous layer wasremoved. The organic layer was concentrated under vacuum, and theresulting residue was purified by silica gel column chromatography toprovide the title compound. MS (m/z) 726.1 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 7.69-7.55 (m), 7.55-7.42 (m), 7.16-7.06 (m), 7.07-6.96(m), 6.89 (d), 6.60 (tt), 6.44 (dd), 6.20 (d), 6.16 (d), 6.08 (s),5.69-5.53 (m), 5.29 (s), 5.26 (d), 4.95-4.85 (m), 4.64 (q), 4.59-4.46(m), 4.36-4.19 (m), 3.94-3.76 (m), 3.64-3.54 (m), 3.18 (s), 3.17 (s),3.01-2.84 (m), 2.78-2.68 (m), 1.86-1.82 (m), 1.38 (s), 1.34 (s), 1.26(s), 1.23 (s), 1.15 (s).

Step 3. tert-Butyl(S)-(1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamido)-1-(2,2,2-trifltioroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate

tert-Butyl(S)-(1-(3-(3-amino-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(37.89 g, 52.18 mmol) was dissolved in methylene chloride (380 mL) withstirring at ambient temperature. To it was added triethylamine (21.82mL, 156.54 mmol) followed by slow addition of methanesulfonyl chloride(8.08 mL, 104.36 mmol). When the reaction was complete, water (200 mL)was added and stirred for about 0.5 hours. The organic layer wasseparated and the aqueous layer was extracted with methylene chlorideonce. The combined organic layers were washed with water and brine,dried over MgSO₄, filtered and concentrated to a small volume. Hexaneswas added. The liquid suspension was decanted. The remaining solid wasdried under reduced pressure to afford the title compound. MS (m/z):882.69 [M+H]⁺. ¹H NMR (400 MHz, Methanol-d₄) δ 7.87 (d), 7.83 (d), 7.76(s), 7.74 (s), 7.69 (s), 7.67 (s), 7.65 (s), 7.52-7.47 (m), 7.46 (s),7.37 (d), 7.33 (d), 7.11-7.03 (m), 4.79-4.55 (m), 4.51 (t), 4.36 (dt),4.20-4.05 (m), 3.64 (s), 3.62 (s), 3.60 (s), 3.59 (s), 3.23 (s), 3.04(d), 3.01 (d), 2.95-2.83 (m), 1.81 (s), 1.34 (s), 1.29 (s), 0.98 (s).

Step 4.(S)—N—(7-(2-(1-Amino-2-(3,5difluorophenyl)ethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide

To tert-Butyl(S)-(1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate(39 g, 44 mmol) dissolved in methylene chloride (120 mL) was addedtrifluoroacetic acid (80 mL). The reaction mixture was stirred atambient temperature for about 50 minutes. The reaction mixture wasdiluted with methylene chloride and slowly poured into ice coldsaturated aqueous NaHCO₃. The organic layer was separated, washed withwater and brine, dried over MgSO₄, filtered and concentrated to drynessto afford the title compound. MS (m/z): 782.84 [M+H]⁺. ¹H NMR (400 MHz,Chloroform-d) δ 7.61 (d), 7.54-7.44 (m), 7.40 (d), 7.33 (d), 7.20 (d),6.66-6.57 (m), 6.44 (d), 6.33 (d), 6.17 (d), 4.64 (s), 3.68 (s), 3.64(s), 3.61 (s), 3.55 (s), 3.19 (s), 3.05 (dd), 2.85-2.72 (m), 1.86 (s),1.62 (s).

Step 5.N—((S)-1-(3-(4-Chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3b5,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide

(S)—N—(7-(2-(1-Amino-2-(3,5-difluorophenypethyl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-4-chloro-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)-N-(methylsulfonyl)methanesulfonamide(1757 mg, 2.25 mmol),2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)aceticacid (Intermediate 3, 666 mg, 2.36 mmol), and HATU(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate) (854 mg, 2.25 mmol) were charged in a roundbottom flask and dissolved in DMF (dimethylformamide) (10.0 mL). To thesolution was added N,N-diisopropylethylamine (0.80 mL, 4.49 mmol) at arapid dropwise rate. After addition was complete, the reaction mixturewas stirred at room temperature for about 15 minutes to provide theintermediateN—((S)-1-(3-(4-chloro-3-(N-(methylsulfonyl)methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamidewhich was not isolated (MS (m/z) 1046.65 [M+H]⁺). To the solution wasadded 2N aq. sodium hydroxide solution (5.0 mL). The mixture was stirredat room temperature for about 30 minutes. The reaction mixture waspartitioned between water and ethyl acetate. The organic layer wascollected and washed with two portions of 5% lithium chloride solutionfollowed by brine. The organic layer was isolated, dried over sodiumsulfate, filtered, and concentrated under vacuum. The resulting residuewas purified by silica gel column chromatography to yield the titlecompound as an amorphous solid. MS (m/z) 968.24 [M+H]⁺. ¹H NMR (400 MHz,Methanol-d₄) δ 7.87-7.57 (m), 7.33-7.09 (m), 6.80-6.70 (m), 6.54 (d),6.47 (d), 6.37-6.19 (m), 5.02-4.94(m), 4.90-4.70 (m), 4.70-4.51 (m),3.94 (dq), 3.32-3.28 (m), 3.23 (d), 3.07 (dd, J=13.1, 7.6 Hz), 2.93(dd), 2.68-2.35 (m), 1.81 (s), 1.41 (q), 1.12-1.00 (m). ¹⁹F NMR (377MHz, Methanol-d₄) δ −63.65, −71.78 (t), −72.35 (t), −82.75 (dd), −105.70(ddd), −111.73−− 113.10 (m).

Example 2N—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamideSodium Salt, Form II

Compound 1 (100 mg) was mixed with 35 mg (1 eq) NaOH (from a MeOHsolution containing 11.8% NaOH). The sample was stirred in 0.5 mLisopropyl acetate (i-PrOAc) to form a solution. It was dried to becomesolid, and then dissolved in 0.5 mL i-PrOAc. Heptane (0.15 mL) was addedas antisolvent and the sample was stirred at about 21° C. for about 2hours to become a thick slurry. The sample was diluted by 1.5 mLi-PrOAc, stirred for about 16 hours, filtered, and dried at about 50° C.The dried sample was analyzed and verified as the sodium salt ofCompound 1, Form II.

Example 3 Polymorph Screening ofN—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenypethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4] cyclo penta [1,2-c] pyrazol-1-yl)acetamide Sodium Salt

A polymorph screening of the sodium salt described in Example 2 wasconducted by stirring 20 to 40 mg of the sodium salt, Form II in 0.2 mLof various solvents at about 21° C., and the results are shown in Table1.

TABLE 1 After 1 day After 1 week Experiment Solvent Wet form Afterdrying* Wet form After drying* 1 Water Form II Form II Form II — 2EtOH/H2O Solution — Solution — 3 MeCN MeCN Solvate Form I MeCN SolvateForm I 4 Methanol Solution — Solution — 5 Ethanol EtOH Solvate 1 FormIII EtOH Solvate 2 Form I 6 Acetone Acetone Solvate Form III AcetoneSolvate — 7 IPA IPA Solvate 1 Form III IPA Solvate 2 Form I 8 MEK MEKSolvate — MEK Solvate Amorphous 9 MIBK MIBK Solvate — MIBK Solvate FormII 10 DCM Mesophase Form I Mesophase — 11 THF Mesophase Mesophase/Mesophase — amorphous 12 2-MeTHF 2-MeTHF Solvate Form II 2-MeTHF Solvate— 13 EtOAc EtOAc Solvate Form II EtOAc Solvate — 14 i-PrOAc i-PrOAcSolvate Form II i-PrOAc Solvate — 15 MTBE MTBE Solvate Form II MTBESolvate — 16 Toluene Toluene Solvate Form II Toluene Solvate — *Dryingconditions: about 50° C. and under vacuum. — refers to no dataavailable.

It was observed that the sodium salt formed solvates or mesophases withalmost all solvents shown in Table 1, except for water. In ethanol andisopropanol, there were two solvates for each solvent with the onescrystallized initially being the metastable ones. After drying, thesolvates from acetonitrile, ethanol (EtOH Solvate 2), IPA (IPA Solvate2), and DCM (mesophase) became Form I; the solvates from MIBK,2-methyltetrahydrofuran, ethyl acetate, isopropyl acetate, methylt-butyl ether, and toluene became Form II; and the solvates fromacetone, ethanol (EtOH Solvate 1), and IPA (IPA Solvate 1) became FormIII.

Form I

As shown in Table 1, the sodium salt Form I was obtained by firstforming solvates of the sodium salt of Compound 1 in solutions such asacetonitrile, ethanol (EtOH Solvate 2), isopropanol (IPA Solvate 2), ordichloromethane, followed by desolvation at about 50° C. under vacuum.

The XRPD pattern of the sodium salt of Compound 1, crystalline Form I isshown in FIG. 1. A list of 2-theta peaks is provided in Table 2 below.

TABLE 2 Peak No. 2-theta (°) Rel. Int. (%) 1 5.6 17 2 6.6 100 3 9.7 4 410.9 8 5 13.4 10 6 16.8 17 7 17.1 22 8 19.0 3 9 19.4 4 10 19.8 3 11 20.35 12 21.1 4 13 21.4 6 14 21.8 13 15 22.7 3 16 24.1 8 17 24.7 4 18 25.7 419 26.9 9 20 28.9 5 21 31.6 3

The DSC thermogram of the sodium salt of Compound 1, crystalline Form Iis shown in FIG. 2 and exhibited a melting onset of about 218° C.

Form II

As shown in Table 1, the sodium salt of Compound 1, crystalline Form IIwas obtained by first forming solvates of the sodium salt of Compound 1in solutions such as MIBK, 2-methyltetrahydrofuran, ethyl acetate,isopropyl acetate, methyl t-butyl ether, and toluene, followed bydesolvation at about 50° C. under vacuum.

The XRPD pattern of the sodium salt of Compound 1, crystalline Form IIis shown in FIG. 3. A list of 2-theta peaks is provided in Table 3below.

TABLE 3 Peak No. 2-theta Rel. Int. (%) 1 5.4 59 2 7.0 100 3 11.1 55 412.9 12 5 16.3 23 6 17.7 52 7 19.2 42 8 21.2 31 9 22.6 61 10 24.0 32 1125.1 25 12 27.7 25 13 28.8 9 14 30.6 7 15 35.2 9

The DSC thermogram of the sodium salt of Compound 1, crystalline Form IIis shown in FIG. 4 and exhibited a melting onset of about 222° C.

Form III

As shown in Table 1, the sodium salt of Compound 1, crystalline Form IIIwas obtained by first forming solvates of the sodium salt of Compound 1in solutions such as acetone, ethanol (EtOH Solvate 1), and IPA (IPASolvate 1), followed by desolvation at about 50° C. under vacuum.

The XRPD pattern of the sodium salt of Compound 1, crystalline Form IIIis shown in FIG. 5. A list of 2-theta peaks is provided in Table 4below.

TABLE 4 Peak No. 2-theta (°) Rel. Int. (%) 1 5.9 40 2 7.1 100 3 9.1 6 411.6 44 5 14.1 15 6 15.4 24 7 17.2 31 8 17.5 22 9 18.4 62 10 19.5 36 1120.2 26 12 20.8 33 13 22.2 49 14 23.3 18 15 24.6 15 16 25.5 22 17 27.223 18 28.2 9 19 29.7 15 20 30.1 19 21 31.8 5 22 35.3 10 23 35.9 8

The DSC thermogram of the sodium salt of Compound 1, crystalline FormIII is shown in FIG. 6 and exhibited a melting onset of about 213° C.

Example 4N—((S)-1-(3-(4-Chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenypethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamidePotassium Salt

Compound 1 (1.0 g) was combined with KOH (1 equivalent, 50% solution inwater) and methanol (2 mL) to obtain a solution. The solution was driedto dryness at about 50° C. to afford a solid.

Example 5 Polymorph Screening ofN—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenypethyl)-2-43bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamidePotassium Salt

A polymorph screening of the potassium salt described in Example 4 wasconducted by stirring 20 to 40 mg of amorphous Compound 1 potassium saltat about 21° C. in 0.2 mL of various solvents: water, EtOH/H₂O (1:1)mixture, acetonitrile, methanol, ethanol, acetone, IPA, MEK, MIBK, DCM,THF, 2-MeTHF, EtOAc, i-PrOAc, MTBE, and toluene. After stirring forabout 1 week, the samples were either solutions or amorphous. 20 to 50μL of heptane were added to the solution samples and they were stirredfor one more week. No crystalline solids were obtained. The samples wereplaced in a refrigerator at about 0 to about 5° C. for about 3 days, andthe sample in 2-MeTHF showed apparently birefringent particles bypolarized light microscopy (PLM); however, XRPD analysis of the wetsolids showed almost no crystalline peaks. This sample was used to seeda 500 mg crystallization batch from THF, which was then used to seed theother samples from the original screening experiments. After stirringfor about 16 hours at about 21° C., the sample in MEK showedbirefringence and was confirmed to be crystalline as wet solids by XRPD,as shown in FIG. 7. However, after drying, the salt lost crystallinityand became amorphous.

Example 6N—((S)-1-(3-(4-Chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenypethyl)-2-43bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamideMethanesulfonic Acid (Mesylate) Salt or Cocrystal, Form I

Methanesulfonic acid (1 eq.) was stirred with 400 μL of a toluenesolution containing 50 mg of Compound 1 at about 21° C. The acid was notmiscible; therefore, about 50 μL MeCN was added to assist withdissolution. After stirring for a few hours, the sample crystallized andwas isolated as the methanesulfonic acid (mesylate) salt or cocrystal ofCompound 1, crystalline Form I, as shown in FIG. 8.

Example 7 Polymorph Screening ofN—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenypethyl)-2-43bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamideMethanesulfonic Acid (Mesylate) Salt or Cocrystal

A polymorph screening was conducted by stirring 20 to 100 mg of themethanesulfonic acid salt or cocrystal of Compound 1, crystalline Form Iin 0.2 mL of various solvents at about 21° C. Slurries were obtained formost of the samples except Samples 5, 6, 8, 10, 11, 12, to which 50 to150 μL of heptane were added as antisolvent, and Sample 4, to which MTBEwas added as antisolvents. After stirring for about 16 hours, Samples 4,5, 6, 8, 11, 13 remained as solutions and the rest were slurries.Additional antisolvents were added to the solution samples. Samples 6,8, 10, 13 were seeded with Sample 9, and were stirred for about 16hours. The Samples 8 and 13 also crystallized after stirring for about16 hours. XRPD analysis were conducted for the wet solids and the solidsdried at about 50° C. under vacuum, and the results are shown in Table5.

TABLE 5 Sample Solvent Wet form After drying 1 Water Form I + amorphous— 2 EtOH/H2O Sticky substance — 3 MeCN MeCN Solvate Form I 4Methanol/MTBE Solution — 5 Ethanol/heptane Solution — 6 Acetone/heptaneSolution — 7 IPA IPA Solvate Deliquesced before drying 8 MEK/heptaneForm II Form II 9 MIBK Form II Form II 10 DCM/heptane DCM Solvate FormIII 11 THF/heptane Solution — 12 2-MeTHF/heptane Form II Form II 13EtOAc/heptane Form II — 14 i-PrOAc Form II — 15 MTBE Form II — 16Toluene Form II — — refers to no data available. Solvent-antisolventcombinations are listed as solvent/antisolvent.

It was observed that the methanesulfonic acid (mesylate) salt orcocrystal formed solvates with acetonitrile, IPA, and DCM. After drying,the acetonitrile solvate became crystalline Form I, and the DCM solvatebecame crystalline Form III. The IPA solvate was not analyzed in thedrying study because it deliquesced while being held at ambientconditions before drying. A non-solvated form, crystalline Form II, wasobtained from solvents such as MEK/heptane,2-methyltetrahydrofuran/heptane, ethyl acetate/heptane, isopropylacetate, MTBE, and toluene.

Form I

The methanesulfonic acid (mesylate) salt or cocrystal of Compound 1,crystalline Form I was prepared by drying the solids from a mixture oftoluene and MeCN. It was reproduced in the polymorph screening withouttoluene as shown in Table 5. In toluene alone, the methanesulfonic acid(mesylate) salt or cocrystal did not form a solvate.

The XRPD pattern of the methanesulfonic acid (mesylate) salt orcocrystal of Compound 1, crystalline Form I, is shown in FIG. 8. A listof 2-theta peaks is provided in Table 6 below.

TABLE 6 Peak No. 2-theta Rel. Int. (%) 1 9.8 10 2 12.9 15 3 15.4 100 416.0 12 5 16.5 10 6 17.0 17 7 17.5 10 8 18.4 26 9 18.8 25 10 19.7 87 1120.2 36 12 20.9 52 13 21.7 12 14 22.4 25 15 22.9 27 16 23.5 45 17 24.430 18 24.8 24 19 25.3 26 20 26.0 19 21 26.9 17 22 27.2 20 23 28.0 9 2429.0 12 25 29.4 16 26 30.3 7 27 30.8 18 28 35.3 9

The DSC thermogram of the methanesulfonic acid (mesylate) salt orcocrystal of Compound 1, crystalline Form I is shown in FIG. 9 andexhibited a melting onset of about 130° C.

Form II

As shown in Table 5, the methanesulfonic acid (mesylate) salt orcocrystal of Compound 1, crystalline Form II was obtained from solventsincluding MEK/heptane, 2-methyltetrahydrofuran/heptane, ethylacetate/heptane, isopropyl acetate, MTBE, and toluene. The XRPD patternof the methanesulfonic acid (mesylate) salt or cocrystal of Compound 1,crystalline Form II is shown in FIG. 10. A list of 2-theta peaks isprovided in Table 7 below.

TABLE 7 Peak No. 2-theta Rel. Int. (%) 1 8.7 17 2 10.8 11 3 13.0 15 414.8 12 5 15.6 12 6 17.5 29 7 18.1 23 8 18.8 26 9 19.3 100 10 19.9 27 1120.6 68 12 21.3 58 13 21.7 38 14 22.4 19 15 22.8 27 16 23.2 19 17 23.519 18 24.2 25 19 25.3 19 20 27.1 26 21 28.3 20 22 29.2 23 23 30.1 11 2430.8 9 25 32.2 23 26 32.9 8 27 35.8 6 28 36.6 8 29 37.8 7 30 38.9 5

The DSC thermogram of the methanesulfonic acid (mesylate) salt orcocrystal of Compound 1, crystalline Form II is shown in FIG. 11 andexhibited a melting onset of about 165° C.

Dichloromethane Solvate

As shown in Table 5, the dichloromethane solvate form of themethanesulfonic acid (mesylate) salt of Compound 1 was obtained byslurrying the mesylate crystalline salt Form I in DCM. The DCM solvateform was used to obtain single crystal for X-ray diffraction (XRD) toconfirm the structure of the methanesulfonic acid salt, shown in FIG.12. The single crystals of the dichloromethane solvate were prepared asfollows: a solution containing 0.06 g of the methanesulfonic acid(mesylate) salt of Compound 1 dissolved in 1 mL DCM was cooled to about21° C., seeded with DCM solvate seeds from Example 7, and rod crystalswere obtained.

The SCXRD data confirmed a mono salt of methanesulfonic acid and twomolecules of DCM for each molecule of Compound 1. The parameters of thecrystal lattice are shown below in Table 8.

TABLE 8 Temperature 100.0 K Crystal system Orthorhombic Space groupP212121 Unit cell dimensions a = 9.7483(9) Å α = 90° b = 22.5139(16) Å β= 90° c = 23.3580(17) Å γ = 90° Volume 5126.4(7) Å³ Z 4 Density(calculated) 1.599 g/cm³

Form III

The methanesulfonic acid (mesylate) salt or cocrystal of Compound 1,crystalline Form III was obtained by desolvating the dichloromethanesolvate at about 50° C. under vacuum. The XRPD pattern of the mesylatesalt or cocrystal, crystalline Form III is shown in FIG. 13. A list of2-theta peaks is provided in Table 9 below.

TABLE 9 Peak No. 2-theta Rel. Int. (%) 1 8.2 34 2 11.3 13 3 12.8 25 414.5 8 5 15.7 29 6 16.2 14 7 16.9 39 8 18.6 18 9 18.9 14 10 19.2 20 1119.8 32 12 20.1 51 13 20.7 18 14 21.3 30 15 21.8 100 16 22.0 40 17 22.664 18 23.1 5 19 24.0 23 20 24.4 16 21 24.7 39 22 25.6 23 23 26.0 9 2426.4 25 25 27.1 31 26 27.6 12 27 28.6 6 28 29.7 14 29 30.2 17 30 30.9 631 32.7 13 32 33.9 12 33 34.9 13 34 36.0 5 35 38.3 17 36 38.8 5

The DSC thermogram of the methanesulfonic acid (mesylate) salt orcocrystal of Compound 1, crystalline Form III is shown in FIG. 14 andexhibited a melting onset of about 141° C.

Form IV (Hydrate)

The methanesulfonic acid (mesylate) salt or cocrystal of Compound 1,crystalline Form IV is a hydrate and was obtained by stirring themesylate salt or cocrystal of Compound 1, crystalline Form III in waterfor about 16 hours. The XRPD pattern of the mesylate salt or cocrystalof Compound 1, crystalline Form IV is shown in FIG. 15. A list of2-theta peaks is provided in Table 10 below.

TABLE 10 Peak No. 2-theta Rel. Int. (%) 1 7.9 90 2 8.8 7 3 11.1 29 412.1 14 5 12.7 27 6 14.1 11 7 15.4 19 8 15.7 13 9 16.9 26 10 18.2 10 1119.2 18 12 19.7 19 13 20.0 28 14 20.4 21 15 21.2 100 16 21.5 21 17 21.737 18 22.1 16 19 23.1 6 20 23.9 15 21 24.2 13 22 24.6 9 23 25.4 14 2426.6 19 25 26.9 11 26 28.0 8 27 28.7 13 28 29.1 12 29 29.4 13 30 30.4 731 33.3 6 32 34.0 7 33 38.2 8

Example 8N—((S)-1-(3-(4-Chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenypethyl)-2-43bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamideEthanesulfonic Acid (Esylate) Salt or Cocrystal

The crystalline ethanesulfonic acid (esylate) salt or cocrystal ofCompound 1 was prepared as follows: Ethanesulfonic acid (1 equivalent)was stirred with 400 μL of a toluene solution containing 50 mg ofCompound 1 at about 21° C. The acid was not miscible; therefore, 50 μLMeCN was added to assist with dissolution. The resulting solution wasseeded with the methanesulfonic acid (mesylate) salt or cocrystal ofCompound 1, crystalline Form I and crystallized after stirring for about16 hours. The solids were dried under vacuum at about 50° C., and XRPDanalysis was performed and is shown in FIG. 16. A list of 2-theta peaksis provided in Table 11 below.

TABLE 11 Peak No. 2-theta Rel. Int. (%) 1 9.1 10 2 10.4 4 3 12.7 42 413.3 14 5 15.2 100 6 16.1 6 7 16.5 8 8 16.9 10 9 17.2 10 10 18.5 15 1118.8 33 12 19.2 28 13 19.5 70 14 19.9 33 15 20.5 50 16 21.1 11 17 21.518 18 22.4 55 19 23.2 25 20 25.3 30 21 25.6 31 22 26.5 8 23 27.1 21 2427.9 11 25 28.8 7 26 29.4 5 27 30.9 6 28 32.2 6 29 34.7 5 30 35.0 6 3136.9 6 32 39.5 8

The DSC thermogram of the ethanesulfonic acid (esylate) salt orcocrystal of Compound 1 is shown in FIG. 17 and exhibited a meltingonset of about 119° C.

Example 9N—((S)-1-(3-(4-Chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamideBenzenesulfonic Acid (Besylate) Salt

The crystalline benzenesulfonic acid salt or cocrystal of Compound 1 wasprepared as follows: Benzenesulfonic acid (1 equivalent) was stirredwith 400 μL of a toluene solution containing 50 mg of Compound 1 atabout 21° C. The acid was not fully dissolved; therefore, 50 μL MeCN wasadded to assist with dissolution. The resulting solution was seeded withthe methanesulfonic acid salt or cocrystal of Compound 1, crystallineForm I and crystallized after stirring for about 16 hours. The solidswere dried under vacuum at about 50° C., and XRPD analysis was performedand is shown in FIG. 18. A list of 2-theta peaks is provided in Table 12below.

TABLE 12 Peak No. 2-theta Rel. Int. (%) 1 7.5 17 2 8.5 15 3 10.7 5 412.9 17 5 13.6 21 6 14.3 9 7 15.1 6 8 15.7 19 9 16.7 48 10 17.0 90 1117.4 18 12 17.9 10 13 18.5 44 14 18.9 65 15 19.1 51 16 19.4 37 17 20.0100 18 20.3 35 19 20.7 38 20 21.3 40 21 21.7 91 22 22.5 16 23 22.9 25 2423.1 37 25 23.6 14 26 24.2 30 27 24.5 13 28 25.0 36 29 25.4 19 30 25.728 31 26.6 42 32 27.2 18 33 27.9 15 34 28.6 7 35 29.3 12 36 30.4 30 3731.1 12 38 31.5 8 39 32.2 20 40 32.6 18 41 33.1 10 42 34.2 8 43 34.8 944 36.2 7 45 38.9 12

The DSC thermogram of the benzenesulfonic acid (besylate) salt orcocrystal of Compound 1 is shown in FIG. 19.

Example 10N—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenypethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamideHydrochloric Acid Salt or Cocrystal Form I

The hydrochloric acid salt or cocrystal of Compound 1, crystalline FormI was prepared as follows: about 50 mg of Compound 1 was mixed with 0.5mL 37% HCl (about 100 eq.) and 0.25 mL MeCN. The mixture was sonicatedbriefly and crystalline solids appeared. The solids were isolated byfiltration and were dried under vacuum at about 50° C. The dried solidswere designated as the hydrochloric acid salt or cocrystal of Compound1, crystalline Form I.

The XRPD pattern of the hydrochloric acid salt or cocrystal, crystallineForm I is shown in FIG. 20. A list of 2-theta peaks is provided in Table13 below.

TABLE 13 Peak No. 2-theta Rel. Int. (%) 1 6.9 12 2 8.2 8 3 9.0 16 4 9.424 5 10.5 7 6 11.0 6 7 12.1 17 8 12.6 48 9 13.0 18 10 13.8 20 11 14.3 7112 15.4 76 13 15.7 27 14 16.4 100 15 17.0 14 16 17.6 22 17 18.2 64 1818.7 72 19 19.2 66 20 20.1 88 21 20.8 63 22 21.2 17 23 21.6 93 24 22.128 25 22.5 80 26 23.4 27 27 23.8 86 28 24.4 8 29 25.2 62 30 25.5 21 3125.9 28 32 26.8 45 33 27.6 33 34 27.8 27 35 28.2 51 36 28.8 28 37 29.721 38 30.6 9 39 31.0 10 40 31.5 26 41 32.2 19 42 33.2 8 43 34.3 10 4435.8 7 45 39.3 6

The DSC thermogram of the hydrochloric acid salt or cocrystal ofCompound 1, crystalline Form I is shown in FIG. 21 and exhibited amelting onset of about 101° C.

Form II

The hydrochloric acid salt or cocrystal of Compound 1, crystalline FormII was prepared by slurrying about 5 mg the hydrochloric acid salt orcocrystal of Compound 1, crystalline Form I in MTBE and toluene forabout 16 hours. XRPD showed that the solids in MTBE and tolueneexhibited a new pattern, which was designated as crystalline Form II.After drying at about 50° C., an XRPD analysis of the solids from MTBEand toluene showed another new pattern, which was designated ascrystalline Form III.

The hydrochloric acid salt or cocrystal of Compound 1, crystalline FormII was also prepared by mixing about 50 mg of Compound 1 with 0.5 mL 37%HCl (about 100 eq.) and 0.25 mL acetone. The mixture was sonicatedbriefly and crystalline solids of the hydrochloric acid salt orcocrystal of Compound 1, Form II were observed. The XRPD pattern of thehydrochloric acid salt or cocrystal of Compound 1, crystalline Form IIis shown in FIG. 22. A list of 2-theta peaks is provided in below inTable 14.

TABLE 14 Peak No. 2-theta Rel. Int. (%) 1 9.6 3 2 10.5 10 3 12.3 29 412.7 10 5 13.3 12 6 15.1 19 7 16.1 7 8 16.5 6 9 17.2 39 10 17.6 99 1118.1 33 12 18.8 34 13 19.4 19 14 20.3 13 15 20.9 30 16 21.5 30 17 22.338 18 22.6 50 19 23.1 100 20 24.1 22 21 24.5 20 22 24.9 11 23 25.5 38 2426.9 38 25 28.7 6 26 29.3 19 27 32.0 14 28 34.4 13 29 36.6 5

Form III

The hydrochloric acid salt or cocrystal of Compound 1, crystalline FormIII was prepared by drying the hydrochloric acid salt or cocrystal ofCompound 1, crystalline Form II at about 50° C. under vacuum. The XRPDpattern of the hydrochloride salt or cocrystal of Compound 1,crystalline Form III is shown in FIG. 23. A list of 2-theta peaks isprovided in Table 15 below.

TABLE 15 Peak No. 2-theta Rel. Int. (%) 1 9.7 33 2 11.9 12 3 12.9 56 414.0 21 5 14.5 13 6 16.0 33 7 16.7 34 8 17.6 84 9 18.0 100 10 18.5 83 1119.3 79 12 19.7 75 13 21.0 21 14 21.3 37 15 22.1 91 16 23.9 42 17 25.066 18 25.6 49 19 26.5 32 20 27.0 21 21 27.9 10 22 29.2 30 23 30.4 22 2431.8 17 25 32.7 7

The DSC thermogram of the hydrochloric acid salt or cocrystal ofCompound 1, crystalline Form III is shown in FIG. 24 and exhibited amelting onset of about 112° C.

Example 11N—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenypethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamideSulfuric Acid Salt

100 mg of Compound 1 was combined with 10 μL 98% sulfuric acid (1.9 eq.)in 400 μL MTBE. The mixture was sonicated and then stirred at about 50°C. for about 16 hours in an open vial, resulting in crystalline solids.The XRPD pattern of the sulfuric acid salt or cocrystal (vacuum dried atabout 50° C.) is shown in FIG. 25. A list of 2-theta peaks is providedin Table 16 below.

TABLE 16 Peak No. 2-theta Rel. Int. (%) 1 9.0 15 2 11.5 11 3 13.1 27 414.2 28 5 15.3 63 6 15.7 24 7 16.3 91 8 16.9 19 9 18.3 100 10 18.6 33 1119.1 77 12 19.3 56 13 19.8 51 14 20.2 30 15 20.7 13 16 21.4 39 17 21.738 18 22.6 51 19 23.6 43 20 23.9 51 21 24.9 28 22 25.3 22 23 26.4 11 2427.0 24 25 27.7 45 26 28.1 36 27 29.8 21 28 31.5 21 29 33.3 10 30 34.212 31 39.2 7

The DSC thermogram of the sulfuric acid salt or cocrystal of Compound 1is shown in FIG. 26 and exhibited a melting onset of about 169° C.

Representative synthesis of the compounds described herein can also befound in U.S. patent application Ser. No. 15/680,041, filed Aug. 17,2017, which published as U.S. Patent Application No. 2018-0051005 A1 onFeb. 22, 2018, the entire contents of which are incorporated herein byreference in their entireties.

BIOLOGICAL EXAMPLES Example A Test A: Antiviral Assay in MT4 Cells

For the antiviral assay, 0.4 μL of 189× test concentration of 3-foldserially diluted compound in DMSO was added to 40 μL of cell growthmedium (RPMI 1640, 10% FBS, 1% Penicillin-Streptomycin, 1% L-Glutamine,1% HEPES) in each well of 384-well plate (10 concentrations) inquadruplicate.

1 mL Aliquots of MT4 cells were pre-infected for 3 hours at 37° C. with25 μL of cell growth medium (mock-infected) or a fresh 1:250 dilution ofan HIV-IIIb concentrated ABI stock (0.004 m.o.i.). Infected anduninfected cells were diluted in cell growth media and 35 μL (2000cells) was added to each well of the assay plates.

Assay plates were then maintained in a humidified, 5% CO₂ incubator at37° C. After 5 days of incubation, 25 μL of 2× concentratedCellTiter-Glo™ Reagent (catalog # G7573, Promega Biosciences, Inc.,Madison, Wis.) was added to each well of the assay plate. Cell lysis wascarried out by incubating at room temperature for 10 minutes and thenchemiluminescence was read using an Envision plate reader (PerkinElmer).EC₅₀ values were calculated as the compound concentration that caused a50% decrease in luminescence signal, a measure of HIV-1 replication.

As described in Examples B-D, Compound 1 provides advantages compared tostructurally close compounds (herein designated as Compounds A and B)disclosed in U.S. Patent Publication Nos. 2014/0296266A1 and2014/0303164A1:

Example B Test B: Cytotoxicity Assay

Compound cytotoxicity and the corresponding CC₅₀ values was determinedusing the same protocol as described in the antiviral assay (Test A)except that uninfected cells were used.

The compound of the present disclosure demonstrates antiviral activity(Test A) as depicted in Table A in comparison to Compound A and CompoundB.

TABLE A Compound EC₅₀ (nM) CC₅₀ (nM) Compound 1 0.185 30068 Compound A1.715 21839 Compound B 2.991 14491

Example C Test C. Pharmacokinetic Analysis Following IntravenousAdministration to Sprague-Dawley Rats and Beagle Dogs and CynomologousMonkeys Test Article and Formulation

Compound 1 IV administration was formulated in 5% ethanol, 20% PG, 45%PEG 300, 30% pH 2 (0.01N HCl) water at 0.5 mg/mL. Compound A andCompound B intravenous infusion doses were formulated in a sterilesolution of 5% ethanol, 45% PEG 400 and 50% water (pH 2.0) at 0.5 mg/mL.All IV formulations were in solution.

Animals Used

Each rat IV dosing group consisted of 3 male SD rats. At dosing, theanimals generally weighed between 0.317 and 0.355 kg. The animals werefasted overnight prior to dose administration and up to 4 hr afterdosing. Each dog IV dosing group consisted of 3 male, naive beagle dogs.At dosing, the animals weighed ˜10-12 kg. The animals were fastedovernight prior to dose administration and up to 2 hr after dosing.

Each cynomolgus (cyno) monkey IV dosing group consisted of 3 male, naivecyno monkeys At dosing, the animals weighed ˜3.2-4 kg. The animals werefasted overnight prior to dose administration and up to 2 hr afterdosing.

Dosing

For the IV infusion group, the test compound was administered byintravenous infusion over 30 minutes. The rate of infusion was adjustedaccording to the body weight of each animal to deliver a dose of 1 mg/kgat 2 mL/kg.

Sample Collection

Serial venous blood samples (approximately 0.4 mL each for rat and 1.0mL for dog) were taken at specified time points after dosing from eachanimal. The blood samples were collected into Vacutainer™ tubes(Becton-Disckinson Corp, New Jersey, USA) containing EDTA as theanti-coagulant and were immediately placed on wet ice pendingcentrifugation for plasma. Centrifugation began within 1 hour ofcollection. All samples were placed into 96-well tubes and maintained ondry ice prior to storage at approximately −70° C.

Determination of the Concentrations of Compound 1 in Plasma

An LC/MS/MS method was used to measure the concentration of testcompounds in plasma.

Calculations

Non-compartmental pharmacokinetic analysis was performed on the plasmaconcentration-time data. A summary of pharmacokinetic parameters areshown in Tables B and C below.

TABLE B Rat Rat Rat Dog Dog Dog Cyno Cyno Cyno CL V_(ss) t_(1/2) CLV_(ss) t_(1/2) CL Vss t_(1/2) Compound (L/h/kg) (L/kg) (h) (L/h/kg)(L/kg) (h) (L/h/kg) (L/kg) (h) Compound 1 0.05 1.8 28 0.07 1.6 22 0.242.7 12 Compound A 0.50 1.0 2 0.25 0.8 4 0.45 1.18 2.3 Compound B 0.431.4 3 0.28 1.3 6 0.42 1.59 3.4 CL: observed clearance; Vss: volume ofdistribution at steady state; t_(1/2): terminal half-life

TABLE C Rat Dog Cyno Rat AUC_(inf) Dog AUC_(inf) Cyno AUC_(inf) CompoundC_(max) (μM · h) C_(max) (μM · h) C_(max) (μM · h) Compound 1 1.8 19 2.214.8 1.3 4.5 Compound A 1.4 2.7 2.1 5 1.8 2.6 Compound B 1.1 2.7 1.4 4.31.4 2.9 AUC_(inf): Area Under the Curve from t = 0 to infinity; C_(max):Maximum plasma concentration

Example D Test D. Metabolic Stability in Cultured Human LiverHepatocytes

Radiolabelled test compounds, wherein tritium was introduced into thestructure in place of one or more hydrogens, were prepared according toknown methods in the art.

The radiolabelled compounds were incubated in pooled cryopreservedhepatocytes at a substrate concentration of 0.25 μM and radioactivityconcentration of 10 μCi/mL. The final hepatocyte concentration was 1million cells/mL. The hepatocyte/compound reaction mixture was dissolvedin InVitroGRO™ KHB buffer (catalog # Z99074, BioreclamationlVT, Inc.,Baltimore, Md.) at pH 7.4. The incubations were performed in duplicate.A cell free control and a positive control were included in theincubations. The incubations were carried out with gentle shaking in a37° C. incubator under a humid atmosphere of 95% air/5% CO₂ (v/v).Aliquots (100 mL) were removed after 0, 1, 3, and 6 hours and added to200 mL quenching solution that comprised 0.1% (v/v) TFA in 5% water/95%acetonitrile (v/v). The samples were placed on a shaker for 10 min,followed by centrifugation at 3000 g for 30 min. The samples of thesupernatant were analyzed on a Dionex HPLC/PerkinElmer FlowScintillation Analyzer as described below.

Liquid Chromatography-Radiochromatography

Quantification was done by comparison of radiolabeled metabolites andparent peaks measured on a Radiomatic 625TR Flow Scintillation Analyzercoupled to a Dionex/Chromeleon chromatography system. The column was aPhenomenex Synergi fusion RP (150×4.6 mm, 4 mm) maintained at 32 degreesCelsius. Mobile Phase A consisted of 0.1% (v/v) TFA in 99% water/1%acetonitrile (v/v). Mobile Phase B consisted of 0.1% (v/v) TFA in 5%water/95% acetonitrile (v/v). The flow rate was 1 mL/min using a sampleinjection volume of 100 mL. Gradient was as following: Mobile phase Bwas linearly increased from 2% to 75% over 47 min, maintained at 75% for3 min, changed back to 2%, maintained at 2% for 10 min.

Metabolic stability was determined by measuring the change in relativeabundance of metabolites and parent over time and calculating from itthe rate of disappearance of the parent compound. The stability data wasutilized to calculate predicted human hepatic clearance values accordingto methods known in the art. The predicted human hepatic clearancevalues are shown in Table D below.

TABLE D Predicted Human Hepatic Clearance (L/hr/kg) Compound 1 0.01Compound A 0.09 Compound B 0.04

The following can be deduced from the above comparative data:

Compound 1 is more potent in an HIV antiviral assay relative tocompounds A and B (about 9 and about 16 times more potent,respectively). Compound 1 has a longer in vivo terminal half-life in ratrelative to compounds A and B (about 14 and about 9 times longer,respectively). Compound 1 has a lower in vivo clearance in rat relativeto compounds A and B (about 10 and about 8.6 times lower, respectively).Compound 1 has a longer in vivo terminal half-life in dog relative tocompounds A and B (about 5 and about 4 times longer, respectively).Compound 1 has a lower in vivo clearance in dog relative to compounds Aand B (about 3 and about 4 times lower, respectively). Compound 1 ismore stable in human hepatocytes with a lower predicted hepaticclearance relative to compounds A and B (about 9 and about 4 times morestable, respectively).

The above data demonstrate that Compound 1, has improved antiviralpotency and an improved pharmacokinetic profile (which is demonstratedby longer half-life in rat and dog and lower predicted human clearance)when compared to compounds A and B.

The specific pharmacological responses observed may vary according toand depending on the particular active compound selected or whetherthere are present pharmaceutical carriers, as well as the type offormulation and mode of administration employed, and such expectedvariations or differences in the results are contemplated in accordancewith practice of the present disclosure.

The Examples disclosed herein describe the synthesis of compounds,salts, and crystalline forms disclosed herein as well as intermediatesused to prepare the compounds. It is to be understood that individualsteps described herein may be combined. It is also to be understood thatseparate batches of a compound may be combined and then carried forth inthe next synthetic step.

Formulation Example A

A suspension of Form I of the sodium salt of Compound 1 in 2% poloxamer188 in saline (200 mg/mL) was prepared. The suspension was administeredto dogs subcutaneously at a dose of 6 mg/kg and the pharmacokinetic (PK)profile was determined. FIG. 27 shows a plot of the plasma concentrationof Compound 1 as a function of time. As FIG. 27 shows, Compound 1 hasmeasurable plasma concentrations at day 70 demonstrating extendedrelease pharmacokinetics.

Formulation Example B

A solution of the Form I of the sodium salt of Compound 1 in NMP (200mg/mL) was prepared. The solution was administered to dogssubcutaneously at a dose of 6 mg/kg and the pharmacokinetic (PK) profilewas determined. FIG. 28 shows a plot of the plasma concentration ofCompound 1 as a function of time. As the data shows in FIG. 28, Compound1 has measurable plasma concentrations at day 70 demonstrating extendedrelease pharmacokinetics.

Formulation Example C

A solution formulation containing 200 mg/mL of Compound 1 with 1.2 molarequivalent NaOH to form in situ sodium salt in 10% ethanol, 13% water,and 77% PEG are provided. Subjects were orally dosed with thisformulation at 6 mg/kg. A solution of the Compound 1 in 10% ethanol, 13%water, and 77% PEG 200 (200 mg/mL) with 1.2 molar equivalent NaOH wasprepared to form in situ sodium salt. The solution was administered todogs subcutaneously at a dose of 6 mg/kg and the pharmacokinetic (PK)profile was determined. FIG. 29 shows a plot of the plasma concentrationof Compound 1 as a function of time. As the data shows in FIG. 29,Compound 1 has measurable plasma concentrations at day 28 demonstratingextended release pharmacokinetics.

Formulation Example D

A solution formulation of Compound 1 in 10% ethanol, 13% water, and 77%glycofurol (200 mg/mL) with 1.2 molar equivalent NaOH was prepared toform in situ sodium salt. The solution was administered to dogssubcutaneously at a dose of 6 mg/kg and the pharmacokinetic (PK) profilewas determined. FIG. 30 shows a plot of the plasma concentration ofCompound 1 as a function of time. As the data shows in FIG. 30, Compound1 has measurable plasma concentrations at day 28 demonstrating extendedrelease pharmacokinetics.

All references, including publications, patents, and patent documentsare incorporated by reference herein, as though individuallyincorporated by reference. The present disclosure provides reference tovarious embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the present disclosure.

1. A pharmaceutically acceptable salt, which isN—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamidesodium salt.
 2. A crystalline form of the salt of claim
 1. 3. Thecrystalline form of claim 2, which is selected from crystalline Form I,crystalline Form II, and crystalline Form III.
 4. The crystalline formof claim 3, wherein the crystalline Form I has at least three XRPDpeaks, in terms of 2-theta±0.2°, selected from 5.6°, 6.6°, 10.9°, 13.4°,16.8°, 17.1°, 21.8°, 24.1°, and 26.9°.
 5. The crystalline form of claim3, wherein the crystalline Form is crystalline Form I, wherein thecrystalline Form I has at least three XRPD peaks, in terms of2-theta±0.2°, selected from 5.6°, 6.6°, 10.9°, 13.4°, 16.8°, 17.1°,21.8°, 24.1°, and 26.9°.
 6. The crystalline form of claim 3, wherein thecrystalline Form I is characterized by an XRPD pattern substantially asshown in FIG.
 1. 7. The crystalline form of claim 3, wherein thecrystalline Form I is characterized by a DSC thermogram having a meltingonset of about 218° C.
 8. The crystalline form of claim 3, wherein thecrystalline Form I is characterized by a DSC thermogram substantially asshown in FIG.
 2. 9. The crystalline form of claim 3, wherein thecrystalline Form II has at least three XRPD peaks, in terms of2-theta±0.2°, selected from 5.4°, 7.0°, 11.1°, 17.7°, 19.2°, 21.2°,22.6°, 24.0°, and 27.7°.
 10. The crystalline form of claim 3, whereinthe crystalline Form is crystalline Form II, wherein the crystallineForm II has at least three XRPD peaks, in terms of 2-theta±0.2°,selected from 5.4°, 7.0°, 11.1°, 17.7°, 19.2°, 21.2°, 22.6°, 24.0°, and27.7°.
 11. The crystalline form of claim 3, wherein the crystalline FormII is characterized by an XRPD pattern substantially as shown in FIG. 3.12. The crystalline form of claim 3, wherein the crystalline Form II ischaracterized by a DSC thermogram having a melting onset of about 222°C.
 13. The crystalline form of claim 3, wherein the crystalline Form IIis characterized by a DSC thermogram substantially as shown in FIG. 4.14. The crystalline form of claim 3, wherein the crystalline Form IIIhas at least three XRPD peaks, in terms of 2-theta±0.2°, selected from5.9°, 7.1°, 11.6°, 15.4°, 17.2°, 18.4°, 19.5°, 22.2°, and 27.2°.
 15. Thecrystalline form of claim 3, wherein the crystalline Form is crystallineForm III, wherein the crystalline Form III has at least three XRPDpeaks, in terms of 2-theta±0.2°, selected from 5.9°, 7.1°, 11.6°, 15.4°,17.2°, 18.4°, 19.5°, 22.2°, and 27.2°.
 16. The crystalline form of claim3, wherein the crystalline Form III is characterized by an XRPD patternsubstantially as shown in FIG.
 5. 17. The crystalline form of claim 3,wherein the crystalline Form III is characterized by a DSC thermogramhaving a melting onset of about 213° C.
 18. The crystalline form ofclaim 3, wherein the crystalline Form III is characterized by a DSCthermogram substantially as shown in FIG.
 6. 19-76. (canceled)
 77. Apharmaceutical composition comprising a pharmaceutically acceptable saltof claim 1, and at least one pharmaceutically acceptable excipient. 78.A method of treating or preventing a human immunodeficiency virus (HIV)infection comprising administering a therapeutically effective amount ofthe pharmaceutically acceptable salt of claim 1 to a subject in needthereof.
 79. The method of claim 78, wherein the method comprisesadministering the salt or crystalline form in combination with one, two,three, or four additional therapeutic agents. 80-100. (canceled)
 101. Apharmaceutical composition comprising a crystalline form of claim 2, andat least one pharmaceutically acceptable excipient.